Substituted guanidine compounds

ABSTRACT

The present invention provides a compound of general formula (I) (wherein X is as described in the present description and claims), or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing that compound.

TECHNICAL FIELD

The present invention relates to substituted guanidine compounds, apharmaceutical composition containing the same, and particularlysubstituted guanidine compounds and a pharmaceutical compositioncontaining the same for treating diseases prevented, alleviated and/ortreated by inhibiting VAP-1.

PRIOR ART

Type 2 diabetes is a type of lifestyle disease for which the number ofpatients with this disease has continued to increase in recent years. Aprolonged hyperglycemic state gradually destroys microvessels throughoutthe body, resulting in the risk of causing serious damage to variousorgans including the oculus and kidney. These types of serious damageare referred to as diabetic complications, and among these, preventingthe onset and inhibiting the progression of the three major diabeticcomplications consisting of diabetic neuropathy, diabetic retinopathyand diabetic nephropathy are becoming important issues.

Although the prevention of onset and inhibition of progression ofdiabetic complications are foremost based on the control of bloodglucose level, increases in the activity of VAP-1 (vascular adhesionprotein-1, also referred to as semicarbazide-sensitive amine oxidase(SSAO)) in blood and the correlation thereof with plasma glycosylatedhemoglobin levels have been observed in diabetes patients in recentyears. This enzyme, which is selectively located in vascular tissue,catalyzes deamination of methylamine and aminoacetone, respectivelyproducing formaldehyde and methylglyoxal in addition to H₂O₂ andammonia. Since each of these substances has cytotoxicity, increases inVAP-1 activity in blood are attracting attention as one of the causes ofthe onset of inflammatory diseases or diabetic complications (see, forexample, Non-Patent Documents 1 and 2).

Various VAP-1 enzyme inhibitors have been reported thus far. A compoundof the following formula:

is described to have VAP-1 inhibitory activity and be useful for theprevention and/or treatment of VAP-1-associated diseases includingvarious types of inflammatory diseases and diabetic complications, andparticularly diabetic nephropathy or diabetic macular edema (see, forexample, Patent Document 1).

Moreover, a compound of the following formula:

is described to have VAP-1 inhibitory activity and be useful for theprevention and/or treatment of VAP-1-associated diseases includingvarious types of inflammatory diseases and diabetic complications, andparticularly diabetic nephropathy or diabetic macular edema (see, forexample, Patent Document 2).

On the other hand, it has also been reported that expression of VAP-1increases in the liver of patients with chronic liver disease, thatsoluble VAP-1 concentration in serum and expression of VAP-1 in theliver of patients with non-alcoholic fatty liver disease increase incomparison with those of patients not having non-alcoholic fatty liverdisease, and that there is a correlation between soluble VAP-1concentration in serum and the severity of fibrosis based on liverbiopsies performed on patients with non-alcoholic fatty liver disease(see, for example, Non-Patent Document 3). On the basis thereof, inaddition to the aforementioned diabetic complications, non-alcoholicfatty liver disease, and particularly non-alcoholic steatohepatitis, isexpected to be prevented, alleviated and/or treated by inhibiting VAP-1.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: International Publication No. WO 2011/034078-   Patent Document 2: International Publication No. WO 2012/124696

Non-Patent Documents

-   Non-Patent Document 1: Diabetologia (1997), 40: 1243-1250-   Non-Patent Document 2: Diabetologia (2002), 45: 1255-1262-   Non-Patent Document 3: The Journal of Clinical Investigation (2015),    2: 501-520

SUMMARY OF INVENTION Problem to be Solved by the Invention

The present invention provides a useful novel compound for treatingdiseases prevented, alleviated and/or treated by inhibiting VAP-1, and apharmaceutical composition containing the same.

Means for Solving the Problem

As a result of conducting extensive research on compounds having VAP-1inhibitory activity, the present inventors found that a series ofsubstituted guanidine compounds, or salts thereof, having afluoropyridine ring at a specific position in the molecule has superiorVAP-1 inhibitory activity and is useful for the treatment of diseasesprevented, alleviated and/or treated by inhibiting VAP-1, andparticularly diabetic nephropathy and non-alcoholic steatohepatitis,thereby leading to completion of the present invention.

The present invention provides the following [1] to [20].

[1] A compound of general formula (I):

wherein,X is a CR¹R², a carbonyl group or a group of formula (Ia):

R¹ and R², independently of each other, are a hydrogen atom, halogenatom, hydroxy group, protected hydroxy group, optionally substitutedC₁-C₆ alkyl group or optionally substituted C₁-C₆ alkoxy group, wherethe term “substituted” refers to being substituted with at least onesubstituent selected from the group consisting of a deuterium atom,halogen atom, hydroxy group and C₁-C₆ alkoxy group,

p and q, independently of each other, are integers from 0 to 3, providedthat the sum of p and q is 2 or more,

or a pharmacologically acceptable salt thereof.

[2] The compound described in [1] or a pharmacologically acceptable saltthereof, wherein R¹ is a hydrogen atom, halogen atom, hydroxy group,optionally substituted C₁-C₆ alkyl group or optionally substituted C₁-C₆alkoxy group, and R² is a hydrogen atom, halogen atom or C₁-C₃ alkylgroup.[3] The compound described in [2] or a pharmacologically acceptable saltthereof, wherein R¹ is a halogen atom, hydroxy group, C₁-C₆ alkoxy groupor C₁-C₆ alkoxy group substituted with at least one deuterium atom.[4] The compound described in [1] or a pharmacologically acceptable saltthereof, wherein p and q, independently of each other, are integers from1 to 2.[5] The compound described in [1] or a pharmacologically acceptable saltthereof, wherein the compound is:

-   2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate,-   3-[6-(3-ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluoro-benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl-carbamimidoylcarbamate,-   2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate or-   2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [6] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [7] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate.    [8] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [9] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [10] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [11] The compound described in [1] or a pharmacologically acceptable    salt thereof, wherein the compound is:-   2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.    [12] The compound described in any of [1] to [11] or a    pharmacologically acceptable salt thereof, wherein the    pharmacologically acceptable salt is a salt of an organic acid.    [13] The compound described in any of [1] to [11] or a    pharmacologically acceptable salt thereof, wherein the    pharmacologically acceptable salt is a salt of a dicarboxylic acid.    [14] A pharmaceutical composition comprising the compound described    in any of [1] to [13], or a pharmacologically acceptable salt    thereof, and at least one type of pharmacologically acceptable    additive.    [15] The pharmaceutical composition described in [14] for treating a    disease prevented, alleviated and/or treated by inhibiting VAP-1.    [16] The pharmaceutical composition described in [15], wherein the    disease is diabetic nephropathy.    [17] The pharmaceutical composition described in [15], wherein the    disease is non-alcoholic steatohepatitis.    [18] The compound described in any of [1] to [13] or a    pharmacologically acceptable salt thereof, for use in treating a    disease prevented, alleviated and/or treated by inhibiting VAP-1.    [19] Use of the compound described in any of [1] to [13] or a    pharmacologically acceptable salt thereof, for producing a    medicament for treating a disease prevented, alleviated and/or    treated by inhibiting VAP-1.    [20] A method for treating a disease prevented, alleviated and/or    treated by inhibiting VAP-1, comprising: administering a    therapeutically effective amount of the compound described in any of    [1] to [13] or a pharmacologically acceptable salt thereof, to a    patient in need thereof.

Effects of the Invention

Since the compound of general formula (I) of the present invention, or apharmacologically acceptable salt thereof, has high VAP-1 inhibitoryactivity and superior pharmacokinetic properties, it is useful intreating a disease prevented, alleviated and/or treated by inhibitingVAP-1, and typically non-alcoholic fatty liver diseases such asnon-alcoholic steatohepatitis, inflammatory diseases such as atopicdermatitis or psoriasis, diabetic complications such as diabeticneuropathy, diabetic retinopathy (and particularly, diabetic macularedema) or diabetic nephropathy, vascular diseases such asatherosclerosis, heart diseases such as myocardial infarction, andmetabolic diseases such as obesity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The meanings of terms used in the present description and claims are asexplained below. Terms used in the present description and claims havethe meanings indicated below unless specifically indicated otherwise.

In the present description, numerical ranges indicated using the symbol“-” indicate a range that includes values indicated before and after the“-” symbol as the minimum and maximum values, respectively, of thatrange.

In the present invention, the compound of general formula (I) includesisotopic isomers thereof. Namely, all or a portion of the atoms of thecompound of general formula (I) may be substituted with isotopic atomscorresponding respectively thereto. An isotopic atom refers to an atomhaving a different mass number from the mass number found in nature.Examples of such isotopic atoms include hydrogen atoms (²H, ³H), carbonatoms (¹³C, ¹⁴C), nitrogen atoms (¹⁵N), and oxygen atoms (¹⁷O, ¹⁸O).Deuterium atoms (²H) in particular may be represented with a “D”. Insuch cases, in the compound of general formula (I), all of the hydrogenatoms at specific locations indicated by D are substituted by deuteriumatoms, and the molecular weight differs from the molecular weightcalculated from the mass numbers found in nature.

“Halogen atom” or “halo” refers to a fluorine atom, chlorine atom,bromine atom or iodine atom either alone or in combination with othergroups.

A “C₁-C₆ alkyl group” refers to a monovalent group of linear orbranched, saturated aliphatic hydrocarbon having 1 to 6 carbon atomseither alone or in combination with other groups. Examples of C₁-C₆alkyl groups include a methyl group, ethyl group, propyl group, butylgroup, pentyl group and hexyl group (including various isomers thereof).A preferable aspect of a C₁-C₆ alkyl group is a C₁-C₄ alkyl group, andexamples thereof include a methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, sec-butyl group andtert-butyl group. A more preferable aspect is a C₁-C₃ alkyl group.

A “C₁-C₆ alkoxy group” refers to a group of —O—R′ (wherein, R′represents the aforementioned C₁-C₆ alkyl group) either alone or incombination with other groups. Examples of C₁-C₆ alkoxy groups include amethoxy group, ethoxy group, propoxy group, butyloxy group, pentyloxygroup and hexyloxy group (including various isomers thereof). Apreferable aspect of a C₁-C₆ alkoxy group is a C₁-C₄ alkoxy group, andexamples thereof include a methoxy group, ethoxy group, propoxy group,isopropoxy group, butyloxy group, isobutyloxy group, sec-butyloxy groupand tert-butyloxy group. A more preferable aspect is a C₁-C₃ alkoxygroup.

An “aryl group” refers to a monovalent group of aromatic hydrocarbonhaving 6 to 10 carbon atoms. Examples of aryl groups include a phenylgroup, 1-naphthyl group and 2-naphthyl group.

A “C₁-C₇ acyl group” refers to a group of —CO—R″ (wherein, R″ representsa hydrogen atom, the aforementioned C₁-C₆ alkyl group or a phenylgroup). Examples of a C₁-C₇ acyl group include a formyl group, acetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group, pivaloyl group, hexanoyl group and benzoyl group.

A “protected hydroxy group” refers to a hydroxy group protected with anappropriate protecting group. The protecting group can be arbitrarilyselected by a person with ordinary skill in the art from among hydroxylgroup protecting groups described in the known art such as ProtectiveGroups in Organic Synthesis, 4th Edition, T. W. Greene and P. G. M.Wuts, ed., John Wiley & Sons Inc. (2006). Examples of protecting groupsof a hydroxyl group include acyl-based protecting groups such as C₁-C₇acyl groups (such as a formyl group, acetyl group, propionyl group,butyryl group, isobutyryl group, valeryl group, isovaleryl group,pivaloyl group, hexanoyl group or benzoyl group), acetal-basedprotecting groups such as a methoxymethyl group, 1-ethoxyethyl group,methylthiomethyl group, benzyloxymethyl group or tetrahydropyranylgroup, silyl-based protecting groups such as a tri(C₁-C₄ alkyl)silylgroup (such as a trimethylsilyl group, triethylsilyl group,triisopropylsilyl group, dimethylisopropylsilyl group ortert-butyldimethylsilyl group), a (C₁-C₄ alkyl)diarylsilyl group (suchas a tert-butyldiphenylsilyl group or diphenylmethylsilyl group), atriarylsilyl group (such as a triphenylsilyl group), or a tribenzylsilylgroup, and benzyl-based protecting groups such as a benzyl group,p-methoxybenzyl group or triphenylmethyl group. Examples of preferableaspects of protecting groups include a C₁-C₇ acyl group,tetrahydropyranyl group, tri(C₁-C₄ alkyl)silyl group, benzyl group,p-methoxybenzyl group and triphenylmethyl group. That is, a preferableaspect of a “protected hydroxy group” is, for example, a C₁-C₇ acyloxygroup, a tetrahydropyranyloxy group, a tri(C₁-C₄ alkyl)silyloxy group, abenzyloxy group, p-methoxybenzyloxy group or a triphenylmethyloxy group.

In the present invention, the phrase “optionally substituted” refers toa certain group being not substituted or being substituted with at leastone substituent selected from a group of given substituents such as thegroup consisting of a deuterium atom, halogen atom, hydroxy group andC₁-C₆ alkoxy group.

In the present invention, a preferable aspect of an “optionallysubstituted C₁-C₆ alkyl group” is an (unsubstituted) C₁-C₆ alkyl groupor C₁-C₆ alkyl group substituted with at least one substituent selectedfrom the group consisting of a deuterium atom, halogen atom, hydroxygroup and C₁-C₆ alkoxy group. A more preferable aspect of an “optionallysubstituted C₁-C₆ alkyl group” is an (unsubstituted) C₁-C₆ alkyl groupor C₁-C₆ alkyl group substituted with at least one substituent selectedfrom the group consisting of a deuterium atom, halogen atom and hydroxygroup. An even more preferable aspect of an “optionally substitutedC₁-C₆ alkyl group” is an (unsubstituted) C₁-C₆ alkyl group or C₁-C₆alkyl group substituted with at least one substituent selected from thegroup consisting of a deuterium atom and halogen atom. A particularlypreferable aspect of an “optionally substituted C₁-C₆ alkyl group” is an(unsubstituted) C₁-C₆ alkyl group or C₁-C₆ alkyl group substituted withat least one substituent selected from the group consisting of adeuterium atom and fluorine atom.

In the present invention, a preferable aspect of an “optionallysubstituted C₁-C₆ alkoxy group” is an (unsubstituted) C₁-C₆ alkoxy groupor C₁-C₆ alkoxy group substituted with at least one substituent selectedfrom the group consisting of a deuterium atom, halogen atom, hydroxygroup and C₁-C₆ alkoxy group. A more preferable aspect of an “optionallysubstituted C₁-C₆ alkoxy group” is an (unsubstituted) C₁-C₆ alkoxy groupor C₁-C₆ alkoxy group substituted with at least one substituent selectedfrom the group consisting of a deuterium atom, halogen atom and hydroxygroup. An even more preferable aspect of an “optionally substitutedC₁-C₆ alkoxy group” is an (unsubstituted) C₁-C₆ alkoxy group or C₁-C₆alkoxy group substituted with at least one substituent selected from thegroup consisting of a deuterium atom and halogen atom. A particularlypreferable aspect of an “optionally substituted C₁-C₆ alkoxy group” isan (unsubstituted) C₁-C₆ alkoxy group or C₁-C₆ alkoxy group substitutedwith at least one substituent selected from the group consisting of adeuterium atom and fluorine atom.

The compound of general formula (I) of the present invention includesstereoisomers thereof (if such stereoisomers exist). Stereoisomers referto isomers having different spatial configurations of atoms, andexamples thereof include optical isomers such as diastereomers andenantiomers, and geometric isomers. For example, in the case thecompound of general formula (I) of the present invention has one or morechiral centers, the compound of general formula (I) of the presentinvention can be present in the form of optically pure enantiomers, amixture of enantiomers such as racemates, optically pure diastereomers,a mixture of diastereomers, racemates of diastereomers or a mixture ofracemates of diastereomers.

Examples of pharmacologically acceptable salts of the compound ofgeneral formula (I) of the present invention include inorganic acidsalts such as hydrochlorides, hydrobromides, hydroiodides, nitrates,sulfates or phosphates, and organic acid salts such as acetates,trifluoroacetates, benzoates, oxalates, malonates, succinates, maleates,fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates,trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates,glutamates or aspartates. Preferable aspects of organic acid saltsconsist of salts of dicarboxylic acids such as oxalates, malonates,succinates, maleates, fumarates and tartrates.

Other examples of pharmacologically acceptable salts of the compound ofgeneral formula (I) of the present invention include metal salts such assodium salts, potassium salts, calcium salts or magnesium salts,inorganic salts such as ammonium salts, and organic amine salts such astriethylamine salts or guanidine salts.

The compound of general formula (I) of the present invention, or apharmacologically acceptable salt thereof, may be a pharmacologicallyacceptable solvate. A preferable aspect of a solvate is a hydrate. Thehydrate may be a product of moisture absorption by the compound ofgeneral formula (I) of the present invention or a pharmacologicallyacceptable salt thereof.

The compound of general formula (I) of the present invention or apharmacologically acceptable salt thereof may exhibit crystalpolymorphism in the case of being a crystal. Crystal polymorphism refersto the same substance having different crystal structures. Each crystalor a mixture thereof at any arbitrary ratio is included in the presentinvention.

The following provides a detailed explanation of embodiments of thepresent invention.

The present invention relates to a compound of general formula (I):

wherein,X is a CR¹R², a carbonyl group or a group of formula (Ia):

R¹ and R², independently of each other, are a hydrogen atom, halogenatom, hydroxy group, protected hydroxy group, optionally substitutedC₁-C₆ alkyl group or optionally substituted C₁-C₆ alkoxy group, wherethe term “substituted” refers to being substituted with at least onesubstituent selected from the group consisting of a deuterium atom,halogen atom, hydroxy group and C₁-C₆ alkoxy group, and

p and q, independently of each other, are integers from 0 to 3, providedthat the sum of p and q is 2 or more,

or to a pharmacologically acceptable salt thereof.

In a specific embodiment, the present invention relates to the compoundof general formula (I) according to the present invention, or apharmacologically acceptable salt thereof, wherein X is CR¹R².Specifically, such a compound is represented by general formula (II)below: General formula (II):

In general formula (II), R¹ and R² are the same as defined in generalformula (I).

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ and R² are eachindependently a hydrogen atom, halogen atom, hydroxy group, optionallysubstituted C₁-C₆ alkyl group or optionally substituted C₁-C₆ alkoxygroup. Here, the “substituted C₁-C₆ alkyl group” or “substituted C₁-C₆alkoxy group” is substituted with at least one substituent selected fromthe group consisting of a deuterium atom, halogen atom, hydroxy groupand C₁-C₆ alkoxy group, is preferably substituted with at least onesubstituent selected from the group consisting of a deuterium atom,halogen atom and hydroxy group, is more preferably substituted with atleast one substituent selected from the group consisting of a deuteriumatom and halogen atom, and is even more preferably substituted with atleast one substituent selected from the group consisting of a deuteriumatom and fluorine atom.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ is a hydrogenatom, halogen atom, hydroxy group, optionally substituted C₁-C₆ alkylgroup or optionally substituted C₁-C₆ alkoxy group.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ is a halogen atom,hydroxy group, C₁-C₆ alkoxy group or C₁-C₆ alkoxy group substituted withat least one deuterium atom.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R² is a hydrogenatom, halogen atom or C₁-C₃ alkyl group.

The “substituted C₁-C₆ alkyl group” or “substituted C₁-C₆ alkoxy group”represented by R¹ and R² is substituted with at least one substituentselected from the group consisting of a deuterium atom, halogen atom,hydroxy group and C₁-C₆ alkoxy group, is preferably substituted with atleast one substituent selected from the group consisting of a deuteriumatom, halogen atom and hydroxy group, is more preferably substitutedwith at least one substituent selected from the group consisting of adeuterium atom and halogen atom, and is even more preferably substitutedwith at least one substituent selected from the group consisting of adeuterium atom and fluorine atom.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ is a hydrogenatom, halogen atom, hydroxy group, optionally substituted C₁-C₆ alkylgroup or optionally substituted C₁-C₆ alkoxy group, R² is a hydrogenatom, halogen atom or C₁-C₃ alkyl group, and the “substituted C₁-C₆alkyl group” or “substituted C₁-C₆ alkoxy group” is substituted with atleast one substituent selected from the group consisting of a deuteriumatom and halogen atom (preferably fluorine atom).

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ is a halogen atom,hydroxy group, C₁-C₆ alkoxy group or C₁-C₆ alkoxy group substituted withat least one deuterium atom, and R² is a hydrogen atom, halogen atom orC₁-C₃ alkyl group.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ and R² are eachindependently a hydrogen atom; fluorine atom, chlorine atom, bromineatom, iodine atom; hydroxy group; acetyloxy group, pivaloyloxy group,tetrahydropyran-2-yloxy group, tert-butyldimethylsilyloxy group,benzyloxy group, p-methoxybenzyloxy group, triphenylmethyloxy group;methyl group, ethyl group, isopropyl group, propyl group, butyl group,pentyl group, hexyl group; methoxy group, ethoxy group, propoxy group,isopropoxy group, butyloxy group, pentyloxy group, hexyloxy group;deuterated methyl group; 2-fluoroethyl group, 2,2-difluoroethyl group,2,2,2-trifluoroethyl group, 3-fluoropropyl group; hydroxymethyl group,2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group,3-hydroxy-2-methylpropyl group, 4-hydroxybutyl group,3-hydroxy-3-methylbutyl group, 3-hydroxy-2,2-dimethyl-propyl group,2,3-dihydroxypropyl group, 3-hydroxy-2-(hydroxymethyl)-propyl group,3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl group, 3,4-dihydroxybutylgroup; methoxymethyl group, ethoxymethyl group, propoxymethyl group,butyloxymethyl group, pentyloxymethyl group, hexyloxymethyl group,methoxyethyl group, ethoxyethyl group, propoxyethyl group, butyloxyethylgroup, pentyloxyethyl group, hexyloxyethyl group, methoxypropyl group,ethoxypropyl group, propoxypropyl group, butoxybutyl group;3-fluoro-2-(hydroxymethyl)propyl group, 2-fluoro-3-hydroxypropyl group;2-hydroxy-3-methoxypropyl group, 3-hydroxy-2-methoxypropyl group,3-hydroxy-2-(methoxymethyl)propyl group, 4-hydroxy-3-methoxybutyl group,2-methoxy-3-(trityloxy)propyl group, 2-acetyloxy-3-methoxypropyl group;deuterated methoxy group; 2-fluoroethoxy group, 2,2-difluoroethoxygroup, 2,2,2-trifluoroethoxy group, 3-fluoropropoxy group;hydroxymethoxy group, 2-hydroxyethoxy group, 2-hydroxypropoxy group,3-hydroxypropoxy group, 3-hydroxy-2-methylpropoxy group, 4-hydroxybutoxygroup, 3-hydroxy-3-methylbutoxy group, 3-hydroxy-2,2-dimethyl-propoxygroup, 2,3-dihydroxypropoxy group, 3-hydroxy-2-(hydroxymethyl)-propoxygroup, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propoxy group,3,4-dihydroxybutyloxy group; methoxymethoxy group, ethoxymethoxy group,propoxymethoxy group, butyloxymethoxy group, pentyloxymethoxy group,hexyloxymethoxy group, methoxyethoxy group, ethoxyethoxy group,propoxyethoxy group, butyloxyethoxy group, pentyloxyethoxy group,hexyloxyethoxy group, methoxypropoxy group, ethoxypropoxy group,propoxypropoxy group, butyloxybutyloxy group;3-fluoro-2-(hydroxymethyl)propoxy group, 2-fluoro-3-hydroxypropoxygroup; or 2-hydroxy-3-methoxypropoxy group, 3-hydroxy-2-methoxypropoxygroup, 3-hydroxy-2-(methoxymethyl)propoxy group,4-hydroxy-3-methoxybutyloxy group, 2-methoxy-3-(trityloxy)propoxy groupor 2-acetyloxy-3-methoxypropoxy group.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ and R² are eachindependently a hydrogen atom; fluorine atom, chlorine atom, bromineatom, iodine atom; hydroxy group; tetrahydropyran-2-yloxy group; methylgroup, ethyl group, isopropyl group, propyl group, butyl group; methoxygroup, ethoxy group, propoxy group, isopropoxy group, butyloxy group;deuterated methyl group; 2-fluoroethyl group, 2,2-difluoroethyl group,2,2,2-trifluoroethyl group; hydroxymethyl group, 2-hydroxyethyl group;methoxymethyl group, methoxyethyl group; deuterated methoxy group;2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxygroup; hydroxymethoxy group, 2-hydroxyethoxy group; or methoxymethoxygroup or methoxyethoxy group.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ and R² are eachindependently a hydrogen atom; fluorine atom; hydroxy group;tetrahydropyran-2-yloxy group; methyl group; methoxy group, ethoxygroup, propoxy group, isopropoxy group; deuterated methoxy group; or2-fluoroethoxy group.

In a specific embodiment, the present invention relates to the compoundof general formula (I) or (II) according to the present invention, or apharmacologically acceptable salt thereof, wherein R¹ is a fluorineatom; hydroxy group; methoxy group, ethoxy group, propoxy group,isopropoxy group; or deuterated methoxy group, and R² is a hydrogenatom; fluorine atom; or methyl group.

In another embodiment, the present invention relates to the compound ofgeneral formula (I) according to the present invention, or apharmacologically acceptable salt thereof, wherein X is a carbonylgroup. Specifically, such a compound is represented by general formula(III) below: General formula (III):

In another embodiment, the present invention relates to the compound ofgeneral formula (I) according to the present invention, or apharmacologically acceptable salt thereof, wherein X is a group offormula (Ia). Specifically, such a compound is represented by generalformula (IV) below: General formula (IV):

In general formula (IV), p and q are the same as defined in generalformula (I).

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p and q are each 1.

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p is 0 and q is 2 (orp is 2 and q is 0).

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p is 1 and q is 2 (orp is 2 and q is 1).

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p is 0 and q is 3 (orp is 3 and q is 0).

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p and q are each 2.

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p is 1 and q is 3 (orp is 3 and q is 1).

In another embodiment, the present invention relates to the compound ofgeneral formula (I) or (IV) according to the present invention, or apharmacologically acceptable salt thereof, wherein p is 2 and q is 3 (orp is 3 and q is 2).

In a specific embodiment, the present invention relates to the compoundof general formula (I), or a pharmacologically acceptable salt thereof,wherein the compound is:

-   2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-1),-   2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-2),-   3-[6-(3-ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-3),-   2-fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-4),-   2-fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-5),-   2-fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-6),-   3-[6-(3-butyloxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-7),-   3-{6-[3-(2,2-difluoroethoxy)azetidin-1-yl]-5-fluoropyridin-3-yl}-2-fluorobenzyl    carbamimidoylcarbamate (I-8),-   2-fluoro-3-{5-fluoro-6-[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]-pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-9),-   2-fluoro-3-{5-fluoro-6-[3-(2-hydroxyethoxy)azetidin-1-yl]-pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-10),-   2-fluoro-3-{5-fluoro-6-[3-(2-methoxyethoxy)azetidin-1-yl]-pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-11),-   2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-12),-   3-[6-(azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-13),-   2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-14),-   3-[6-(3-chloroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-15),-   3-[6-(3-bromoazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-16),-   2-fluoro-3-[5-fluoro-6-(3-iodoazetidin-1-yl)pyridin-3-yl]benzyl    carbamiimidoylcarbamate (I-17),-   3-[6-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluoro-benzyl    carbamimidoylcarbamate (I-18),-   3-[6-(3-chloro-3-fluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-19),-   2-fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-20),-   3-[6-(3-ethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-21),-   2-fluoro-3-[5-fluoro-6-(3-propylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-22),-   2-fluoro-3-[5-fluoro-6-(3-isopropylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-23),-   2-fluoro-3-{5-fluoro-6-[3-(hydroxymethyl)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-24),-   2-fluoro-3-{5-fluoro-6-[3-(methoxymethyl)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-25),-   3-[6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-26),-   3-[6-(3-ethyl-3-methylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-27),-   2-fluoro-3-[5-fluoro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-28),-   2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)-3-methylazetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-29),-   2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-30),-   3-[6-(3-ethyl-3-hydroxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-31),-   2-fluoro-3-[5-fluoro-6-(3-fluoro-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-32),-   2-fluoro-3-[5-fluoro-6-(3-oxoazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-33),-   3-[6-(3,3-dihydroxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-34),-   2-fluoro-3-{5-fluoro-6-[3-hydroxy-3-methoxyazetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate (I-35),-   3-[6-(3,3-dimethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-36),-   3-[6-(3-ethoxy-3-hydroxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-37),-   3-[6-(3-ethoxy-3-methoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-38),-   3-[6-(3,3-diethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate (I-39),-   2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate (I-40),-   2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate (I-41),-   2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-42),-   2-fluoro-3-[5-fluoro-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-43),-   2-fluoro-3-[5-fluoro-6-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-44),-   2-fluoro-3-[5-fluoro-6-(5-oxa-2-azaspiro[3.4]octan-2-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-45),-   2-fluoro-3-[5-fluoro-6-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-46),-   2-fluoro-3-[5-fluoro-6-(6-oxa-2-azaspiro[3.5]nonan-2-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-47), or-   2-fluoro-3-[5-fluoro-6-(7-oxa-2-azaspiro[3.6]decan-2-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate (I-48).

In a specific embodiment, the present invention relates to the compoundof general formula (I), or a pharmacologically acceptable salt thereof,wherein the compound is:

-   2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate,-   3-[6-(3-ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluoro-benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate,-   3-[6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate or-   2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate.-   In a specific embodiment, the present invention relates to    2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzyl    carbamimidoylcarbamate, or a pharmacologically acceptable salt    thereof.

In a specific embodiment, the present invention relates to2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate, or a pharmacologically acceptable salt thereof.

In a specific embodiment, the present invention relates to2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate, or a pharmacologically acceptable salt thereof.

In a specific embodiment, the present invention relates to2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate, or a pharmacologically acceptable salt thereof.

In a specific embodiment, the present invention relates to2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate, or a pharmacologically acceptable salt thereof.

In a specific embodiment, the present invention relates to2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate, or a pharmacologically acceptable salt thereof.

Examples of the compounds of general formula (I) of the presentinvention are listed in [Table 1] to [Table 4]. In the followingformulae I-1 to 1-48, D denotes a deuterium atom.

TABLE 1 Compound No. I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

TABLE 2 Compound No. I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

TABLE 3 Compound No. I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

TABLE 4 Compound No. I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

The following indicates a typical method for producing a compound ofgeneral formula (I) of the present invention, or a pharmacologicallyacceptable salt thereof. Furthermore, the compound of the presentinvention, or a pharmacologically acceptable salt thereof, is notlimited to a compound, or pharmacologically acceptable salt thereof,produced according to the production method indicated below.

In the production method indicated below, in the case the compoundcontains a partial structure (such as a hydroxyl group) that inhibits adesired reaction or is susceptible to side reaction, the desiredreaction can be carried out by introducing a protecting group into thatpartial structure and the target compound can be obtained bysubsequently removing the protecting group. Reactions for introducingand removing protecting groups can be carried out according to methodsroutinely used in synthetic organic chemistry (such as the methoddescribed in Protective Groups in Organic Synthesis, 4th Edition, T. W.Greene and P. G. M. Wuts, ed., John Wiley & Sons Inc. (2006)). Inaddition, specific production methods for individual compounds of thepresent invention are explained later in Examples.

(Production Method 1)

X is a CR¹R², a carbonyl group or a group of formula (Ia):

R¹ and R², independently of each other, are a hydrogen atom, halogenatom, hydroxy group, protected hydroxy group, optionally substitutedC₁-C₆ alkyl group or optionally substituted C₁-C₆ alkoxy group, wherethe term “substituted” refers to being substituted with at least onesubstituent selected from the group consisting of a deuterium atom,halogen atom, hydroxy group and C₁-C₆ alkoxy group, and

p and q, independently of each other, are integers from 0 to 3, with theproviso that the sum of p and q is 2 or more.

Step 1 of Production Method 1 is a step for reacting Compound (1) andguanidine or a guanidine acid salt as Compound (2) in a solvent in thepresence of 1,1′-carbonyldiimidazole to produce a compound of generalformula (I).

Compound (1) can be produced according to Syntheses 1 to 3 describedlater and Reference Examples of the present description.

Examples of guanidine acid salts as Compounds (2) include guanidinehydrochloride, guanidine sulfate and guanidine carbonate.

Compound (2) is known and is available from a reagent supplier such asTokyo Chemical Industry Co., Ltd. The amount of guanidine or guanidineacid salt used based on 1 mole of Compound (1) is normally 0.9 times to5 times the molar amount, and preferably 1.1 times to 3 times the molaramount of Compound (1).

There are no particular limitations on the solvent used provided it doesnot inhibit the reaction and dissolves the raw materials to a certaindegree, and examples thereof include aromatic hydrocarbons such asbenzene, toluene or xylene, halogenated aliphatic hydrocarbons such asmethylene chloride, chloroform or 1,2-dichloroethane, ethers such astetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, nitriles such asacetonitrile or propionitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidone, and arbitrarily mixedsolvents thereof. N,N-dimethylformamide is used preferably. Althoughthere are no particular limitations thereon, the amount of solvent usedis normally 1 time to 20 times, and preferably 2 times to 10 times themass of Compound (1).

The amount of 1,1′-carbonyldiimidazole used based on 1 mole of Compound(1) is normally 0.9 times to 5 times the molar amount, and preferably1.1 times to 3 times the molar amount of Compound (1).

Although variable according to such factors as the types and amountsused of the raw materials, solvent and the like, the reactiontemperature is normally −20° C. to 150° C. and preferably 0° C. to 40°C.

Although variable according to such factors as the reaction temperature,the reaction time is normally 1 minute to 48 hours and preferably 1 hourto 24 hours.

Although the reaction pressure may be suitably set as necessary and thereaction may be carried out under increased pressure, reduced pressureor atmospheric pressure, the reaction pressure is preferably atmosphericpressure. Although the reaction can be carried out in an atmospheresuitably selected as necessary, the reaction atmosphere is preferably anair atmosphere or an inert gas atmosphere such as that of nitrogen orargon.

In the case a protecting group is present in Compound (1), Compound (1)can be further subjected to a deprotection step as necessary.

In the case Compound (1) has at least two different types of protectinggroups, only one type of protecting group can be selectively removed byselecting the deprotection conditions.

Deprotection conditions can be suitably selected according to a methodroutinely used in synthetic organic chemistry (such as the methoddescribed in Protective Groups in Organic Synthesis, 4th Edition, T. W.Greene and P. G. M. Wuts, ed., John Wiley & Sons Inc. (2006)) orExamples of the present description.

The aforementioned Compound (1) can be suitably prepared according to,for example, the following Syntheses 1 to 3 and Reference Examples ofthe present description.

(Synthesis 1)

X is as previously described and Hal represents a halogen atom.

Step 2 of Synthesis 1 is a step for obtaining Compound (5) by reactingCompound (3) and Compound (4) in a solvent and in the presence of abase.

Compound (3) is known and is available from reagent suppliers. Examplesof such compounds include 5-bromo-2,3-difluoropyridine. Alternatively,Compound (3) can be produced from known compounds according to knownmethods.

Compound (4) is known and is available from reagent suppliers. Examplesof such compounds include azetidine, azetidin-3-ol, 3-methylazetidine,3,3-dimethylazetidine, 3-fluoroazetidine, 3,3-difluoroazetidine,2-oxa-6-azaspiro[3,3]heptane, and acid salts thereof. Alternatively,Compound (4) can be produced from known compounds according to knownmethods.

Examples of acid salts as Compounds (4) include hydrochlorides,sulfates, acetates and oxalates.

The amount of Compound (4) used based on 1 mole of Compound (3) isnormally 0.9 times to 5 times the molar amount, and preferably 1.1 timesto 3 times the molar amount of Compound (3).

There are no particular limitations on the solvent used provided it doesnot inhibit the reaction and dissolves the raw materials to a certaindegree, and examples thereof include alcohols such as methanol, ethanol,propanol or isopropanol, aromatic hydrocarbons such as benzene, tolueneor xylene, halogenated aliphatic hydrocarbons such as methylenechloride, chloroform or 1,2-dichloroethane, ethers such astetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, nitriles such asacetonitrile or propionitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidone, sulfoxides such asdimethylsulfoxide, and arbitrarily mixed solvents thereof. Alcohols suchas ethanol, amides such as N,N-dimethylformamide or N-methylpyrrolidone,or sulfoxides such as dimethylsulfoxide are used preferably. Althoughthere are no particular limitations thereon, the amount of solvent usedis normally 1 time to 50 times, and preferably 5 times to 20 times themass of Compound (3).

Examples of base used include alkali metal acetates such as sodiumacetate or potassium acetate, alkali metal carbonates such as sodiumcarbonate, potassium carbonate or cesium carbonate, and organic basessuch as triethylamine or diisopropylethylamine, with potassiumcarbonate, cesium carbonate, triethylamine or diisopropylethylaminebeing preferable. The amount of base used based on 1 mole of Compound(3) is normally 0.9 times to 10 times the molar amount, and preferably 1time to 5 times the molar amount of Compound (3).

Although variable according to such factors as the types and amountsused of the raw materials, solvent and the like, the reactiontemperature is normally 0° C. to 150° C. and preferably 40° C. to 120°C.

Although variable according to such factors as the reaction temperature,the reaction time is normally 1 minute to 48 hours and preferably 0.5hours to 24 hours.

Although the reaction pressure may be suitably set as necessary and thereaction may be carried out under increased pressure, reduced pressureor atmospheric pressure, the reaction pressure is preferably atmosphericpressure. Although the reaction can be carried out in an atmospheresuitably selected as necessary, the reaction atmosphere is preferably anair atmosphere or an inert gas atmosphere such as that of nitrogen orargon.

In the case a functional group (such as a halogen atom, hydroxy group orcarbonyl group) is present in Compound (5), Compound (5) can be furtherconverted into the desired form by reacting the functional group with anappropriate reagent in accordance with a known method (see, for example,Reference Examples 2-1 to 2-5, 8, 9, and 12 to 14).

(Synthesis 2)

PG represents a protecting group, and Y represents a boronic acid groupor boronate ester substituent. Examples of the boronate estersubstituent Y include a diisopropyl boronate group, pinacol boronategroup, neopentyl glycol boronate group and catechol boronate group.

Step 3 of Synthesis 2 is a step for obtaining Compound (7) byintroducing a protecting group onto the hydroxyl group of Compound (6)in a solvent.

Compound (6), namely (2-bromo-3-fluorophenyl)methanol, is known or canbe produced from known compounds according to a known method.

Introduction of a protecting group onto the hydroxyl group can besuitably carried out according to the known art, such as that describedin Protective Groups in Organic Synthesis, 4th Edition, T. W. Greene andP. G. M. Wuts, ed., John Wiley & Sons Inc., or Examples of the presentdescription.

Step 4 of Synthesis 2 is a step for obtaining Compound (8) by reactingCompound (7) with a borylation reagent in the presence of a palladiumcatalyst and base and in a solvent and in an inert gas atmosphere tointroduce a boronic acid group or boronate ester substituent.

The borylation reagent is known or can be produced from known compoundsaccording to a known method. Examples of borylation reagents includetrimethyl borate, triisopropyl borate, bis(pinacolato)diborane,bis(neopentylglycolato)diborane and bis(catecholato)diborane. The amountof the borylation reagent used based on 1 mole of Compound (7) isnormally 0.9 times to 5 times the molar amount, and preferably 1.1 timesto 3 times the molar amount of Compound (7).

There are no particular limitations on the solvent used provided it doesnot inhibit the reaction and dissolves the raw materials, base andcatalyst to a certain degree, and examples thereof include aromatichydrocarbons such as benzene or toluene, ethers such as tetrahydrofuran,1,2-dimethoxyethane or 1,4-dioxane, alcohols such as methanol, ethanol,propanol or isopropanol, amides such as N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidone, sulfoxides such asdimethylsulfoxide, nitriles such as acetonitrile, water, and arbitrarilymixed solvents thereof, with toluene, 1,4-dioxane,N,N-dimethylformamide, dimethylsulfoxide or acetonitrile beingpreferable.

Examples of the inert gas used include nitrogen, helium and argon.

Examples of the palladium catalyst used include organic palladiumcomplexes such as tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium dichloride or1,1′-bis(diphenylphosphino)ferrocene palladium dichloride, with1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride beingpreferable. The amount of palladium used as catalyst based on 1 mole ofCompound (7) is normally 0.0001 time to 1 time the molar amount, andpreferably 0.005 times to 0.3 times the molar amount of Compound (7).

Examples of base used include alkali metal acetates such as sodiumacetate or potassium acetate, alkali metal carbonates such as sodiumcarbonate, potassium carbonate or cesium carbonate, and organic basessuch as triethylamine or diisopropylethylamine, with sodium acetate,potassium acetate or triethylamine being preferable. The amount of baseused based on 1 mole of Compound (7) is normally 1 time to 10 times themolar amount, and preferably 1 time to 5 times the molar amount ofCompound (7).

Although variable according to such factors as the types and amountsused of the raw materials, solvent and the like, the reactiontemperature is normally 0° C. to 200° C. and preferably 30° C. to 150°C.

Although variable according to such factors as the reaction temperature,the reaction time is normally 10 minutes to 120 hours and preferably 0.5hours to 48 hours.

Although the reaction pressure may be suitably set as necessary and thereaction may be carried out under increased pressure, reduced pressureor atmospheric pressure, the reaction pressure is preferably atmosphericpressure.

(Synthesis 3)

X, Y and PG are as previously described.

Step 5 of Synthesis 3 is a so-called Suzuki reaction for obtainingCompound (9) by reacting Compound (5) and Compound (8) in a solvent andin the presence of a base or fluoride and a palladium catalyst in aninert gas atmosphere.

Compound (5) can be produced according to the aforementionedSynthesis 1. Compound (8) can be produced according to theaforementioned Synthesis 2. The amount of Compound (8) used based on 1mole of Compound (5) is normally 0.8 times to 3 times the molar amount,and preferably 0.9 times to 1.5 times the molar amount of Compound (5).

There are no particular limitations on the inert solvent used providedit does not inhibit the reaction and dissolves the raw materials,catalyst and base (or fluoride) to a certain degree, and examplesthereof include aromatic hydrocarbons such as benzene or toluene, etherssuch as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, alcoholssuch as methanol, ethanol, propanol or isopropanol, esters such asmethyl acetate or ethyl acetate, amides such as N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidone, sulfoxides such asdimethylsulfoxide, nitriles such as acetonitrile, water, and arbitrarilymixed solvents thereof, with 1,2-dimethoxyethane, mixed solvent of1,2-dimethoxyethane and water, 1,4-dioxane, mixed solvent of 1,4-dioxaneand water, toluene, mixed solvent of toluene, ethanol and water, ormixed solvent of toluene and water being preferable.

Examples of the inert gas used include nitrogen, helium and argon.

Examples of the palladium catalyst used include metal palladiumcatalysts such as palladium-activated carbon or palladium black, organicpalladium complexes such as tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium dichloride,1,1′-bis(diphenylphosphino)ferrocene palladium dichloride ortris(dibenzylideneacetone)dipalladium, and palladium salts such aspalladium chloride or palladium acetate, withtetrakis(triphenylphosphine)palladium or palladium acetate beingpreferable. The amount of palladium used as catalyst based on 1 mole ofCompound (5) is normally 0.0001 time to 1 time the molar amount, andpreferably 0.005 times to 0.3 times the molar amount of Compound (5).

In the case of using tris(dibenzylideneacetone)dipalladium, palladiumchloride or palladium acetate for the catalyst, it is preferable that anorganic phosphine compound also be present. Examples of organicphosphine compounds used include tri-n-butylphosphine,tri-tert-butylphosphine, tricyclohexylphosphine,butyldi-1-adamantylphosphine, triphenylphosphine, tri(o-tolyl)phosphine,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,1,1′-bis(diphenylphosphino)ferrocene and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene, withtricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphineor 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl being preferable. Theamount of organic phosphine compound used based on 1 mole of palladiumis normally 1 time to 5 times the molar amount, and preferably 1.5 timesto 2.5 times the molar amount of palladium.

Examples of base or fluoride include alkali metal acetates such assodium acetate or potassium acetate, alkali metal carbonates such assodium carbonate, potassium carbonate or cesium carbonate, alkali metalphosphates such as trisodium phosphate or tripotassium phosphate, alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide orpotassium hydroxide, quaternary ammonium hydroxides such astetramethylammonium hydroxide, tetraethylammonium hydroxide ortetrabutylammonium hydroxide, and fluorides such as cesium fluoride,tetramethylammonium fluoride, tetraethylammonium fluoride ortetrabutylammonium fluoride, with sodium carbonate or tripotassiumphosphate being preferable. The amount of base or fluoride used based on1 mole of Compound (5) is normally 1 time to 10 times the molar amount,and preferably 1.5 times to 5 times the molar amount of Compound (5).

Although variable according to such factors as the types and amountsused of the raw materials, solvent and the like, the reactiontemperature is normally 0° C. to 200° C. and preferably 50° C. to 150°C.

Although variable according to such factors as the reaction temperature,the reaction time is normally 10 minutes to 120 hours and preferably 0.5hours to 48 hours.

Although the reaction pressure may be suitably set as necessary and thereaction may be carried out under increased pressure, reduced pressureor atmospheric pressure, the reaction pressure is preferably atmosphericpressure.

Step 6 of Synthesis 3 is a step for obtaining Compound (1) by subjectingCompound (9) to deprotection to remove protecting group PG from Compound(9).

Deprotection conditions can be suitably selected according to a methoddescribed in the known art, such as the aforementioned Protective Groupsin Organic Synthesis, 4th Edition, T. W. Greene and P. G. M. Wuts, ed.,John Wiley & Sons Inc., or Examples of the present description.

Furthermore, in the case Compound (9) has a protecting group other thanprotecting group PG, preferably only protecting group PG is removed bysuitably selecting the deprotection conditions.

Compound (1) used in Production Method 1 is obtained according to theaforementioned Syntheses 1 to 3. However, Compound (1) used in theProduction Method 1 can also be obtained by a reaction scheme other thanthat indicated in the aforementioned Syntheses 1 to 3, by interchangingthe suitable combinations and/or suitable reaction orders of each of thesteps and raw materials indicated in the aforementioned Syntheses 1 to 3and by introducing and/or removing suitable protecting groups.

Although the compound obtained in each step may be isolated and purifiedby known means, the compound may also be used in the subsequent step asit is. Isolation and purification can be carried out using ordinaryprocedures such as filtration, extraction, crystallization and variouscolumn chromatography techniques.

In a specific embodiment, the present invention relates to apharmaceutical composition containing the compound of general formula(I) described in any of the aforementioned specific embodiments, or apharmacologically acceptable salt thereof, and preferably relates to apharmaceutical composition containing the compound of general formula(I) described in any of the aforementioned specific embodiments, or apharmacologically acceptable salt thereof, and at least one type ofpharmacologically acceptable additive.

In a specific embodiment, the present invention relates to apharmaceutical composition containing the compound of general formula(I) described in any of the aforementioned specific embodiments, or apharmacologically acceptable salt thereof, for treating a diseaseprevented, alleviated and/or treated by inhibiting VAP-1, and preferablyrelates to a pharmaceutical composition containing the compound ofgeneral formula (I) described in any of the aforementioned specificembodiments, or a pharmacologically acceptable salt thereof, and atleast one type of pharmacologically acceptable additive, for treating adisease prevented, alleviated and/or treated by inhibiting VAP-1.

In a specific embodiment, the present invention relates to apharmaceutical composition containing the compound of general formula(I) described in any of the aforementioned specific embodiments, or apharmacologically acceptable salt thereof, for treating diabeticnephropathy, and preferably relates to a pharmaceutical compositioncontaining the compound of general formula (I) described in any of theaforementioned specific embodiments, or a pharmacologically acceptablesalt thereof, and at least one type of pharmacologically acceptableadditive, for treating diabetic nephropathy.

In a specific embodiment, the present invention relates to apharmaceutical composition containing the compound of general formula(I) described in any of the aforementioned specific embodiments, or apharmacologically acceptable salt thereof, for treating non-alcoholicsteatohepatitis, and preferably relates to a pharmaceutical compositioncontaining the compound of general formula (I) described in any of theaforementioned specific embodiments, or a pharmacologically acceptablesalt thereof, and at least one type of pharmacologically acceptableadditive, for treating non-alcoholic steatohepatitis.

The pharmaceutical composition containing the compound of generalformula (I), or a pharmacologically acceptable salt thereof, can be inthe form of the compound per se (in the form of a bulk powder), or canbe in the form of a preparation, such as a tablet, capsule, powder,syrup, granule, grain, pill, suspension, emulsion, percutaneous agent,suppository, ointment, lotion, inhalant, ophthalmic solution orinjection, produced by mixing with suitable pharmacologically acceptableadditives and the like, and can be administered orally or parenterally(such as by intravenous, intramuscular, intraperitoneal, transdermal,transnasal, transtracheal, transpulmonary, ophthalmic, intradermal orsubcutaneous administration).

These preparations are produced by known methods using additives such asexcipients, lubricants, binders, disintegrating agents, emulsifiers,stabilizers, correctives, diluents, isotonic agents, buffers, pHadjusters, solubilizers, thickeners, dispersants or preservatives(antiseptics).

Examples of excipients include organic excipients and inorganicexcipients. Examples of organic excipients include sugar derivativessuch as lactose, sucrose, glucose, mannitol or sorbitol, starchderivatives such as cornstarch, potato starch, α-starch or dextrin,cellulose derivatives such as crystalline cellulose, gum arabic, dextranand pullulan. Examples of inorganic excipients include light anhydroussilicic acid, and sulfates such as calcium sulfate.

Examples of lubricants include stearic acid, metal stearates such ascalcium stearate or magnesium stearate, talc, colloidal silica, waxessuch as beeswax or spermaceti, boric acid, adipic acid, sulfates such assodium sulfate, glycol, fumaric acid, sodium benzoate, D,L-leucine,sodium lauryl sulfate, silicic acids such as anhydrous silicic acid orsilicic acid hydrate, and starch derivatives listed as examples of theaforementioned excipients.

Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, and compounds listedas examples of the aforementioned excipients.

Examples of disintegrating agents include cellulose derivatives such aslow substituted hydroxypropyl cellulose, carboxymethyl cellulose,calcium carboxymethyl cellulose or internally crosslinked calciumcarboxymethyl cellulose, crosslinked polyvinylpyrrolidone, andchemically modified starch or cellulose derivatives such ascarboxymethyl starch or sodium carboxymethyl starch.

Examples of emulsifiers include colloidal clay such as bentonite orVeegum, anionic surfactants such as sodium lauryl sulfate, cationicsurfactants such as benzalkonium chloride, and nonionic surfactants suchas polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acidester or sucrose fatty acid ester.

Examples of stabilizers include parahydroxybenzoates such as methylparaben or propyl paraben, alcohols such as chlorobutanol, benzylalcohol or phenyl ethyl alcohol, benzalkonium chloride, phenols such asphenol or cresol, thimerosal, acetic anhydride and sorbic acid.

Examples of correctives include sweeteners such as sodium saccharin oraspartame, acidifiers such as citric acid, malic acid or tartaric acid,and aromatics such as menthol, lemon extract or orange extract.

Examples of diluents include usual diluting compounds such as water,lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethyleneglycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone andmixtures thereof.

Examples of isotonic agents include glycerin, propylene glycol, sodiumchloride, potassium chloride, sorbitol and mannitol.

Examples of buffers include phosphoric acid, phosphates, citric acid,acetic acid and ε-aminocaproic acid.

Examples of pH adjusters include hydrochloric acid, citric acid,phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide,boric acid, borax, sodium carbonate and sodium bicarbonate.

Examples of solubilizers include Polysorbate 80, polyoxyethylenehydrogenated castor oil 60 and macrogol 4000.

Examples of thickeners and dispersants include cellulose polymers suchas hydroxypropyl methyl cellulose or hydroxypropyl cellulose, polyvinylalcohol and polyvinylpyrrolidone. Examples of stabilizers include edeticacid and sodium edetate.

Examples of preservatives (antiseptics) include general purpose sorbicacid, potassium sorbate, benzalkonium chloride, benzethonium chloride,methyl parahydroxybenzoate, propyl parahydroxybenzoate andchlorobutanol, and these preservatives can also be used in combination.

Other suitable additives can also be used corresponding to theadministration form. For example, in the case the compound of generalformula (I) of the present invention, or a pharmacologically acceptablesalt thereof, is in the form of an aerosol for transnasal ortranstracheal administration, carbon dioxide or a chlorofluorocarbon(CFC), such as dichlorodifluoromethane, trichlorofluoromethane ordichlorotetrafluoroethane, can be used for the propellant.

Although variable according to conditions such as the symptoms, age orbody weight of a patient, the dosage of the active ingredient of thepharmaceutical composition of the present invention is 0.001 mg/Kg (andpreferably 0.01 mg/Kg) as the lower limit and 20 mg/Kg (and preferably10 mg/Kg) as the upper limit each per administration in the case of oraladministration, or is 0.0001 mg/Kg (and preferably 0.0005 mg/Kg) as thelower limit and 10 mg/Kg (and preferably 5 mg/Kg) as the upper limiteach per administration in the case of parental administration,administered one to six times per day to an adult corresponding tosymptoms.

In a specific embodiment, the present invention relates to the compoundof general formula (I) described in any of the aforementioned specificembodiments, or a pharmacologically acceptable salt thereof, for use intreating a disease prevented, alleviated and/or treated by inhibitingVAP-1.

In a specific embodiment, the present invention relates to the use ofthe compound of general formula (I) described in any of theaforementioned specific embodiments, or a pharmacologically acceptablesalt thereof, for producing a medicament for treating a diseaseprevented, alleviated and/or treated by inhibiting VAP-1.

In a specific embodiment, the present invention relates to a method fortreating a disease prevented, alleviated and/or treated by inhibitingVAP-1, which includes administering a therapeutically effective amountof the compound of general formula (I) described in any of theaforementioned specific embodiments, or a pharmacologically acceptablesalt thereof, to a patient in need thereof.

In the present invention, the terms “treating” a disease or “treatment”of a disease include (1) preventing a disease, or in other words, notallowing the onset of clinical symptoms of a disease in a subject which,although there is the possibility of having been exposed to the diseaseor been susceptible to the disease, does not yet have or exhibitsymptoms of the disease, (2) suppressing a disease, or in other words,suppressing the onset of a disease or clinical symptoms thereof, or (3)alleviating a disease, or in other words, inducing a temporary orpermanent regression of the disease or clinical symptoms thereof.

In the present invention, a “therapeutically effective amount” refersto, in the case of administering to a subject, an amount of the compoundof general formula (I) of the present invention that (i) treats orprevents a disease, (ii) relieves, improves or eliminates one or moresymptoms of a disease, or (iii) prevents or delays the manifestation ofone or more symptoms of a disease. The therapeutically effective amountvaries according to the type of the compound of general formula (I) ofthe present invention used, the clinical condition of the disease beingtreated, the severity of the disease being treated, the age and relativehealth status of the subject, the administration route and form, thediscretion of the examining physician or veterinarian, and otherfactors.

EXAMPLES

DIOL silica gel in silica gel column chromatography indicatesCHROMATOREX (trade name) DIOL MB 100-40/75 manufactured by Fuji SilysiaChemical Ltd.

Unless otherwise mentioned, ¹H-NMR is indicated by chemical shifts (6)relative to tetramethylsilane as the internal standard (0 ppm), and thecoupling constants (J values) are indicated in Hz unit. The peaksplitting patterns are indicated by the following abbreviations: s:singlet, d: doublet, t: triplet, q: quartet, sext: sextet, sep: septet,br s: broad singlet, m: multiplet.

The abbreviations described in Examples and Reference Examples havegeneral meanings that are usually used in the fields of organicchemistry and pharmaceuticals. Specifically, the abbreviations areunderstood by skilled artisans as follows.

-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   THF: tetrahydrofuran-   CDI: 1,1′-carbonyldiimidazole-   NMP: N-methylpyrrolidone

Example 12-Fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound I-1)

CDI300 mg (1.85 mmol) was added to a DMF (6 mL) solution of{2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol280 mg (0.914 mmol) synthesized in the same manner as in ReferenceExample 6-1, and the mixture was stirred at room temperature for 4hours. Next, guanidine carbonate 331 mg (1.84 mmol) was added, and themixture was stirred at room temperature for 16 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration. Ethyl acetate was added to the solid, and themixture was stirred at 60° C. The solid was then collected by filtrationand dried under reduced pressure to give the title compound 262 mg(0.669 mmol, yield 73%) as a white solid.

Mass spectrum (ESI, m/z): 392[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.14-8.09 (m, 1H), 7.71-7.62(m, 1H), 7.53-7.44 (m, 1H), 7.42-7.35 (m, 1H), 7.30-7.23 (m, 1H), 5.05(s, 2H), 4.43-4.20 (m, 3H), 4.00-3.87 (m, 2H), 3.26 (s, 3H).

Example 22-Fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate (Compound I-2)

CDI 330 mg (2.04 mmol) was added to a DMF (6 mL) solution of(2-fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}phenyl)methanol308 mg (0.996 mmol) synthesized in the same manner as in ReferenceExample 6-2, and the mixture was stirred at room temperature for 3hours. Next, guanidine carbonate 368 mg (2.04 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 326 mg (0.827 mmol, yield 83%) as a white solid.

Mass spectrum (ESI, m/z): 395[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.15-8.09 (m, 1H), 7.70-7.61(m, 1H), 7.51-7.44 (m, 1H), 7.42-7.35 (m, 1H), 7.30-7.24 (m, 1H), 5.05(s, 2H), 4.37-4.29 (m, 3H), 3.97-3.90 (m, 2H).

Example 33-[6-(3-Ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate (Compound I-3)

CDI 335 mg (2.07 mmol) was added to a DMF (6 mL) solution of{3-[6-(3-ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol328 mg (1.02 mmol) synthesized in the same manner as in ReferenceExample 6-3, and the mixture was stirred at room temperature for 5hours. Next, guanidine carbonate 369 mg (2.05 mmol) was added, and themixture was stirred at room temperature for 27 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 375 mg (0.925 mmol, yield 90%) as a white solid.

Mass spectrum (ESI, m/z): 406[M+l]+.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.13-8.09 (m, 1H), 7.70-7.62(m, 1H), 7.51-7.44 (m, 1H), 7.42-7.36 (m, 1H), 7.31-7.23 (m, 1H), 5.06(s, 2H), 4.50-4.40 (m, 1H), 4.37-4.29 (m, 2H), 3.98-3.89 (m, 2H), 3.46(q, J=7.0 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H).

Example 42-Fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate (Compound I-4)

CDI 150 mg (0.925 mmol) was added to a DMF (8 mL) solution of(2-fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}phenyl)methanol156 mg (0.461 mmol) synthesized in the same manner as in ReferenceExample 6-4, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 166 mg (0.921 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 170 mg (0.402 mmol, yield 87%) as a white solid.

Mass spectrum (ESI, m/z): 424[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.14-8.10 (m, 1H), 7.71-7.63(m, 1H), 7.52-7.44 (m, 1H), 7.42-7.35 (m, 1H), 7.31-7.23 (m, 1H), 5.05(s, 2H), 4.65-4.59 (m, 1H), 4.54-4.47 (m, 2H), 4.39-4.30 (m, 2H),4.01-3.91 (m, 2H), 3.76-3.61 (m, 2H).

Example 52-Fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound I-5)

CDI 181 mg (1.12 mmol) was added to a DMF (6 mL) solution of{2-fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol187 mg (0.559 mmol) synthesized in the same manner as in ReferenceExample 6-5, and the mixture was stirred at room temperature for 3hours. Next, guanidine carbonate 202 mg (1.12 mmol) was added, and themixture was stirred at room temperature for 16 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 197 mg (0.470 mmol, yield 84%) as a white solid.

Mass spectrum (ESI, m/z): 420[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.13-8.09 (m, 1H), 7.71-7.62(m, 1H), 7.52-7.44 (m, 1H), 7.43-7.35 (m, 1H), 7.31-7.23 (m, 1H), 5.06(s, 2H), 4.47-4.41 (m, 1H), 4.36-4.30 (m, 2H), 3.95-3.90 (m, 2H), 3.36(t, J=6.6 Hz, 2H), 1.59-1.48 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

Example 62-Fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound I-6)

CDI 518 mg (3.19 mmol) was added to a DMF (8 mL) solution of{2-fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol534 mg (1.60 mmol) synthesized in the same manner as in ReferenceExample 6-6, and the mixture was stirred at room temperature for 2hours. Next, guanidine 573 mg (3.18 mmol) carbonate was added, and themixture was stirred at room temperature for 21 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 524 mg (1.25 mmol, yield 78%) as a white solid.

Mass spectrum (ESI, m/z): 420[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.14-8.09 (m, 1H), 7.69-7.63(m, 1H), 7.52-7.44 (m, 1H), 7.42-7.36 (m, 1H), 7.31-7.22 (m, 1H), 5.06(s, 2H), 4.56-4.50 (m, 1H), 4.38-4.32 (m, 2H), 3.93-3.87 (m, 2H),3.71-3.61 (m, 1H), 1.12 (d, J=6.1 Hz, 6H).

Example 72-Fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate (Compound 1-40)

CDI 330 mg (2.04 mmol) was added to a DMF (4 mL) solution of[2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)phenyl]methanol340 mg (0.903 mmol) synthesized in the same manner as in ReferenceExample 6-7, and the mixture was stirred at room temperature for 1 hour.Next, guanidine carbonate 330 mg (1.83 mmol) was added, and the mixturewas stirred at room temperature for 16 hours. After the completion ofthe reaction, water was added to the reaction mixture, and the mixturewas stirred at room temperature. The precipitated solid was collected byfiltration. Toluene was added to the solid, and the mixture wasconcentrated under reduced pressure and dried under reduced pressure togive the title compound 317 mg (0.687 mmol, yield 76%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.15-8.09 (m, 1H), 7.71-7.62(m, 1H), 7.52-7.45 (m, 1H), 7.43-7.35 (m, 1H), 7.32-7.23 (m, 1H), 5.06(s, 2H), 4.71-4.63 (m, 2H), 4.40-4.29 (m, 2H), 4.03-3.96 (m, 2H),3.86-3.74 (m, 1H), 3.49-3.43 (m, 1H), 1.85-1.39 (m, 6H).

Example 82-Fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound I-12)

2 N HCl/ethanol 1.40 mL (2.80 mmol) was added to an ethanol (6 mL)suspension of2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate 317 mg (0.687 mmol) synthesized in the samemanner as in Example 7, and the mixture was stirred at room temperaturefor 30 minutes. After the completion of the reaction, triethylamine0.400 mL (2.87 mmol) was added, and the mixture was concentrated underreduced pressure. The concentrated residue was purified by silica gelcolumn chromatography (eluting solvent; dichloroethane:methanol). Thefraction including the title compound was concentrated under reducedpressure. Ethyl acetate was added to the concentrated residue, and themixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 187 mg (0.496 mmol, yield 72%) as a white solid.

Mass spectrum (ESI, m/z): 378[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.13-8.09 (m, 1H), 7.70-7.61(m, 1H), 7.53-7.44 (m, 1H), 7.43-7.35 (m, 1H), 7.31-7.23 (m, 1H), 5.06(s, 2H), 4.64-4.57 (m, 1H), 4.36-4.28 (m, 2H), 3.92-3.83 (m, 2H).

Example 9 3-[6-(Azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate (Compound I-13)

CDI 302 mg (1.86 mmol) was added to a DMF (6 mL) solution of{3-[6-(azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol 257mg (0.930 mmol) synthesized in the same manner as in Reference Example6-8, and the mixture was stirred at room temperature for 2 hours. Next,guanidine carbonate 335 mg (1.86 mmol) was added, and the mixture wasstirred at room temperature for 20 hours. After the completion of thereaction, water was added to the reaction mixture, and the mixture wasstirred at room temperature. The precipitated solid was collected byfiltration and dried under reduced pressure to give the title compound306 mg (0.847 mmol, yield 91%) as a white solid.

Mass spectrum (ESI, m/z): 362[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.12-8.08 (m, 1H), 7.67-7.59(m, 1H), 7.52-7.44 (m, 1H), 7.42-7.34 (m, 1H), 7.30-7.21 (m, 1H), 5.05(s, 2H), 4.20-4.01 (m, 4H), 2.45-2.24 (m, 2H).

Example 102-Fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound I-14)

CDI 180 mg (1.11 mmol) was added to a DMF (6 mL) solution of{2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]phenyl}methanol158 mg (0.537 mmol) synthesized in the same manner as in ReferenceExample 6-9, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 201 mg (1.12 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 182 mg (0.480 mmol, yield 89%) as a white solid.

Mass spectrum (ESI, m/z): 380[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.18-8.12 (m, 1H), 7.76-7.66(m, 1H), 7.53-7.45 (m, 1H), 7.43-7.36 (m, 1H), 7.31-7.24 (m, 1H),5.69-5.36 (m, 1H), 5.06 (s, 2H), 4.55-4.36 (m, 2H), 4.26-4.09 (m, 2H).

Example 113-[6-(3,3-Difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate (Compound I-18)

CDI 163 mg (1.01 mmol) was added to a DMF (6 mL) solution of(3-(6-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-3-yl)-2-fluorophenyl)methanol157 mg (0.503 mmol) synthesized in the same manner as in ReferenceExample 6-10, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 181 mg (1.01 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give of thetitle compound 143 mg (0.360 mmol, yield 72%) as a white solid.

Mass spectrum (ESI, m/z): 398[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.23-8.15 (m, 1H), 7.81-7.75(m, 1H), 7.54-7.46 (m, 1H), 7.45-7.37 (m, 1H), 7.32-7.25 (m, 1H), 5.06(s, 2H), 4.66-4.43 (m, 4H).

Example 122-Fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound 1-20)

CDI 285 mg (1.76 mmol) was added to a DMF (6 mL) solution of{2-fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]phenyl}methanol255 mg (0.878 mmol) synthesized in the same manner as in ReferenceExample 6-11, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 317 mg (1.76 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. Next, methylene chloridewas added, and the mixture was stirred at room temperature. Theprecipitated solid was collected by filtration and was dried underreduced pressure to give the title compound 272 mg (0.725 mmol, yield82%) as a white solid.

Mass spectrum (ESI, m/z): 376[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.12-8.07 (m, 1H), 7.66-7.58(m, 1H), 7.51-7.34 (m, 1H), 7.41-7.34 (m, 1H), 7.29-7.21 (m, 1H), 5.05(s, 2H), 4.34-4.15 (m, 2H), 3.81-3.63 (m, 2H), 2.88-2.78 (m, 1H), 1.25(d, J=6.8 Hz, 3H).

Example 133-[6-(3,3-Dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate (Compound 1-26)

CDI 279 mg (1.72 mmol) was added to a DMF (6 mL) solution of{3-[6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol262 mg (0.861 mmol) synthesized in the same manner as in ReferenceExample 6-12, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 310 mg (1.72 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture andfollowed by extraction with methylene chloride. The organic layer waswashed with water and dried over anhydrous sodium sulfate. The mixturewas filtered and the filtrate was concentrated under reduced pressure.The concentrated residue was purified by silica gel columnchromatography (DIOL silica gel, eluting solvent; hexane:ethyl acetate)to give the title compound 255 mg (0.655 mmol, yield 76%) as a whitesolid.

Mass spectrum (ESI, m/z): 390[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.11-8.07 (m, 1H), 7.65-7.59(m, 1H), 7.50-7.44 (m, 1H), 7.42-7.35 (m, 1H), 7.30-7.23 (m, 1H), 5.05(s, 2H), 3.86-3.79 (m, 4H), 1.30 (s, 6H).

Example 142-Fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate (Compound I-41)

CDI 281 mg (1.73 mmol) was added to a DMF (6 mL) solution of[2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)phenyl]methanol338 mg (0.866 mmol) synthesized in the same manner as in ReferenceExample 6-13, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 313 mg (1.74 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 311 mg (0.654 mmol, yield 76%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.15-8.08 (m, 1H), 7.72-7.63(m, 1H), 7.52-7.44 (m, 1H), 7.43-7.35 (m, 1H), 7.31-7.23 (m, 1H),5.12-5.01 (m, 2H), 4.90-4.81 (m, 1H), 4.22-4.08 (m, 2H), 4.05-3.92 (m,2H), 3.89-3.79 (m, 1H), 3.60-3.45 (m, 1H), 1.90-1.35 (m, 9H).

Example 152-Fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound 1-30)

At 0° C., 2 N HCl/ethanol 1.6 mL (3.20 mmol) was added to an ethanol (4mL) suspension of2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate 311 mg (0.654 mmol) synthesized in the samemanner as in Example 14, and the mixture was stirred at room temperaturefor 2 hours. After the completion of the reaction, triethylamine 0.55 mL(3.95 mmol) and water were added, and the mixture was stirred. Theprecipitated solid was collected by filtration and was dried underreduced pressure to give the title compound 211 mg (0.539 mmol, yield82%) as a white solid.

Mass spectrum (ESI, m/z): 392[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.13-8.08 (m, 1H), 7.69-7.61(m, 1H), 7.51-7.44 (m, 1H), 7.42-7.35 (m, 1H), 7.29-7.22 (m, 1H), 5.06(s, 2H), 4.09-3.85 (m, 4H), 1.47 (s, 3H).

Example 162-Fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate (Compound 1-42)

CDI 104 mg (0.641 mmol) was added to a DMF (6 mL) solution of{2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]phenyl}methanol102 mg (0.320 mmol) synthesized in the same manner as in ReferenceExample 6-14, and the mixture was stirred at room temperature for 2hours. Next, guanidine carbonate 115 mg (0.638 mmol) was added, and themixture was stirred at room temperature for 20 hours. After thecompletion of the reaction, water was added to the reaction mixture, andthe mixture was stirred at room temperature. The precipitated solid wascollected by filtration and dried under reduced pressure to give thetitle compound 102 mg (0.253 mmol, yield 79%) as a white solid.

Mass spectrum (ESI, m/z): 404[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆+D₂O) δ: 8.13-8.09 (m, 1H), 7.70-7.61(m, 1H), 7.51-7.43 (m, 1H), 7.43-7.35 (m, 1H), 7.31-7.21 (m, 1H), 5.05(s, 2H), 4.74 (s, 4H), 4.34-4.26 (m, 4H).

Reference Example 1 1-(5-Bromo-3-fluoropyridin-2-yl)azetidin-3-ol(Reference Compound 1)

Triethylamine 14 mL (100 mol) was added to an ethanol (70 mL) solutionof 5-bromo-2,3-difluoropyridine 7.56 g (39.0 mmol) and azetidin-3-olhydrochloride 5.00 g (45.6 mol), and the mixture was stirred at 55° C.for 3 hours. After the completion of the reaction, water 70 mL was addedto the reaction mixture. The mixture was concentrated under reducedpressure to approximately halve the solvent, and was thereafter stirredat room temperature. The precipitated solid was collected by filtrationand was dried under reduced pressure to give the title compound 8.06 g(32.6 mol, yield 84%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.03-8.00 (m, 1H), 7.81-7.76 (m,1H), 5.69 (d, J=6.4 Hz, 1H), 4.67-4.48 (m, 1H), 4.34-4.16 (m, 2H),3.86-3.68 (m, 2H).

Reference Example 2-15-Bromo-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine (Reference Compound2-1)

At 0° C., 55% sodium hydride 91 mg (2.09 mmol) was added in portions toa DMF (6 mL) solution of 1-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-ol300 mg (1.21 mmol) synthesized in the same manner as in ReferenceExample 1, and the mixture was stirred at 0° C. for 30 minutes. Next,iodomethane 0.15 mL (2.40 mmol) was added at 0° C., and the mixture wasstirred at room temperature for 1 hour. After the completion of thereaction, saturated aqueous ammonium chloride solution was added to thereaction mixture, and followed by extraction with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous sodiumsulfate. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The concentrated residue was purified by silicagel column chromatography (eluting solvent; hexane:ethyl acetate) togive the title compound 297 mg (1.14 mmol, yield 94%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-7.99 (m, 1H), 7.83-7.76 (m,1H), 4.45-4.12 (m, 3H), 3.95-3.77 (m, 2H), 3.24 (s, 3H).

Reference Example 2-25-Bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine (ReferenceCompound 2-2)

The reaction was performed by the method described in Reference Example2-1, except that iodomethane was replaced by iodomethane-d₃.Consequently, the title compound (yield 93%) was obtained as a whitesolid.

Mass spectrum (ESI, m/z): 264, 266[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆₎ δ: 8.06-7.99 (m, 1H), 7.83-7.76 (m,1H), 4.36-4.20 (m, 3H), 3.91-3.83 (m, 2H).

Reference Example 2-3)5-Bromo-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridine (Reference Compound2-3)

The reaction was performed by the method described in Reference Example2-1, except that iodomethane was replaced by iodoethane. Consequently,the title compound (yield 91%) was obtained as a white solid.

Mass spectrum (ESI, m/z): 275, 277[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.03-8.01 (m, 1H), 7.82-7.77 (m,1H), 4.45-4.35 (m, 1H), 4.30-4.21 (m, 2H), 3.91-3.81 (m, 2H), 3.44 (q,J=7.0 Hz, 2H), 1.13 (t, J=7.0 Hz, 3H).

Reference Example 2-4 5-Bromo-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridine(Reference Compound 2-4)

The reaction was performed by the method described in Reference Example2-1, except that iodomethane was replaced by 2-fluoroethylmethanesulfonate synthesized in the same manner as in Reference Example7. Consequently, the title compound (yield 47%) was obtained as yellowoil.

Mass spectrum (ESI, m/z): 293, 295[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-8.01 (m, 1H), 7.84-7.78 (m,1H), 4.64-4.57 (m, 1H), 4.52-4.44 (m, 2H), 4.32-4.20 (m, 2H), 3.94-3.83(m, 2H), 3.74-3.58 (m, 2H).

Reference Example 2-55-Bromo-3-fluoro-2-(3-propoxyazetidin-1-yl)pyridine (Reference Compound2-5)

The reaction was performed by the method described in Reference Example2-1, except that iodomethane was replaced by iodopropane. Consequently,the title compound (yield 53%) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 289, 291 [M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-8.00 (m, 1H), 7.84-7.76 (m,1H), 4.46-4.35 (m, 1H), 4.31-4.21 (m, 2H), 3.89-3.82 (m, 2H), 3.37-3.28(m, 2H), 1.52 (sext, J=7.3 Hz, 2H), 0.88 (t, J=7.3 Hz, 3H).

Reference Example 3[3-Bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (ReferenceCompound 3)

(Tert-butyl)dimethylsilyl chloride 22 g (0.15 mol) and imidazole 14 g(0.21 mol) were added to a THF (200 mL) solution of(3-bromo-2-fluorophenyl)methanol 25 g (0.12 mol). The mixture wasstirred at room temperature for 5 hours and was allowed to stand at roomtemperature for 2 days. After the completion of the reaction, water wasadded to the reaction mixture and followed by extraction with ethylacetate. The organic layer was washed with water, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated underreduced pressure. The concentrated residue was purified by silica gelcolumn chromatography (eluting solvent; hexane:ethyl acetate) to givethe title compound 35 g (0.11 mol, yield 92%) as colorless oil.

Mass spectrum (CI, m/z): 319, 321[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 7.65-7.59 (m, 1H), 7.48-7.42 (m,1H), 7.22-7.15 (m, 1H), 4.78 (s, 2H), 0.90 (s, 9H), 0.09 (s, 6H).

Reference Example 4 Tert-butyl{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]oxy}dimethylsilane(Reference Compound 4)

1,4-Dioxane (100 mL) solution of[(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane 14.4 g (45.0mmol) synthesized in the same manner as in Reference Example 3,bis(pinacolato)diborane 12.6 g (49.6 mmol) and potassium acetate 6.00 g(61.1 mmol) was degassed and purged with nitrogen. Next,[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride 1.84 g(2.25 mmol) was added. Under a stream of argon, the mixture was stirredat 100° C. for 20 hours. After the completion of the reaction, thereaction mixture was filtered through Celite, water was added, andfollowed by extraction with ethyl acetate. The organic layer was washedwith water, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The concentratedresidue was purified by silica gel column chromatography (elutingsolvent; hexane:ethyl acetate) to give the title compound 9.64 g (26.3mmol, yield 43%) as light yellow oil.

Mass spectrum (CI, m/z): 367[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 7.60-7.52 (m, 2H), 7.25-7.17 (m,1H), 4.74 (s, 2H), 1.29 (s, 12H), 0.90 (s, 9H), 0.09 (s, 6H).

Reference Example 5-15-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine(Reference Compound 5-1)

1,2-Dimethoxyethane (10 mL) suspension of5-bromo-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine 297 mg (1.14 mmol)synthesized in the same manner as in Reference Example 2-1, tert-butyl{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]oxy}dimethylsilane420 mg (1.15 mmol) synthesized in the same manner as in ReferenceExample 4 and 2 M aqueous sodium carbonate solution 1.45 mL (2.90 mmol)was degassed and purged with nitrogen. Next,tetrakis(triphenylphosphine)palladium (0) 131 mg (0.113 mmol) was added.Under a stream of argon, the mixture was stirred at 80° C. for 3 hours.After the completion of the reaction, water was added to the reactionmixture and followed by extraction with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theconcentrated residue was purified by silica gel column chromatography(eluting solvent; hexane:ethyl acetate) to give the title compound 399mg (0.949 mmol, yield 83%) as yellow oil.

Mass spectrum (ESI, m/z): 421[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.09 (m, 1H), 7.69-7.61 (m,1H), 7.49-7.38 (m, 2H), 7.32-7.23 (m, 1H), 4.80 (s, 2H), 4.39-4.28 (m,3H), 3.97-3.89 (m, 2H), 3.26 (s, 3H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-25-(3-{[(Tert-butyldimethylsilyl)oxy]methyl)}-2-fluorophenyl)-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine(Reference Compound 5-2)

1,4-Dioxane (15 mL)-water (7 mL) suspension of5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine 298 mg (1.13mmol) synthesized in the same manner as in Reference Example 2-2,tert-butyl{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]oxy}dimethylsilane480 mg (1.31 mmol) synthesized in the same manner as in ReferenceExample 4 and sodium carbonate 355 mg (3.35 mmol) was degassed andpurged with nitrogen. Next, tetrakis(triphenylphosphine)palladium (0) 67mg (0.058 mmol) was added. Under a stream of argon, the mixture wasstirred at 80° C. for 4 hours. After the completion of the reaction,water was added to the reaction mixture and followed by extraction withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The concentrated residue was purified by silicagel column chromatography (eluting solvent; hexane:ethyl acetate) togive the title compound 464 mg (1.10 mmol, yield 97%) as colorless oil.

Mass spectrum (ESI, m/z): 424[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.09 (m, 1H), 7.70-7.61 (m,1H), 7.48-7.39 (m, 2H), 7.31-7.25 (m, 1H), 4.80 (s, 2H), 4.37-4.28 (m,3H), 3.98-3.89 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-35-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridine(Reference Compound 5-3)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridine synthesized in thesame manner as in Reference Example 2-3. Consequently, the titlecompound (yield 98%) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 435[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.09 (m, 1H), 7.69-7.61 (m,1H), 7.50-7.39 (m, 2H), 7.32-7.24 (m, 1H), 4.80 (s, 2H), 4.48-4.39 (m,1H), 4.37-4.28 (m, 2H), 3.98-3.87 (m, 2H), 3.46 (q, J=7.0 Hz, 2H), 1.15(t, J=7.0 Hz, 3H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-45-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-[3-(2-fluoroethoxy)azetidin-1-yl]pyridine(Reference Compound 5-4)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridine synthesized in thesame manner as in Reference Example 2-4. Consequently, the titlecompound (yield 86%) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 453[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.16-8.09 (m, 1H), 7.71-7.61 (m,1H), 7.51-7.40 (m, 2H), 7.33-7.23 (m, 1H), 4.80 (s, 2H), 4.64-4.59 (m,1H), 4.55-4.46 (m, 2H), 4.38-4.28 (m, 2H), 3.99-3.92 (m, 2H), 3.76-3.60(m, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-55-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-propoxyazetidin-1-yl)pyridine(Reference Compound 5-5)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-3-fluoro-2-(3-propoxyazetidin-1-yl)pyridine synthesized in thesame manner as in Reference Example 2-5. Consequently, the titlecompound (yield 91%) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 449[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.09 (m, 1H), 7.69-7.61 (m,1H), 7.47-7.40 (m, 2H), 7.32-7.24 (m, 1H), 4.80 (s, 2H), 4.47-4.38 (m,1H), 4.36-4.27 (m, 2H), 3.97-3.86 (m, 2H), 3.39-3.28 (m, 2H), 1.54(sext, J=7.1 Hz, 2H), 0.93-0.86 (m, 12H), 0.11 (s, 6H).

Reference Example 5-65-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-isopropoxyazetidin-1-yl)pyridine(Reference Compound 5-6)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-3-fluoro-2-(3-isopropoxyazetidin-1-yl)pyridine synthesized inthe same manner as in Reference Example 8. Consequently, the titlecompound (yield 96%) was obtained as colorless oil Mass spectrum (ESI,m/z): 449[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.09 (m, 1H), 7.70-7.61 (m,1H), 7.49-7.39 (m, 2H), 7.32-7.24 (m, 1H), 4.80 (s, 2H), 4.57-4.47 (m,1H), 4.38-4.30 (m, 2H), 3.94-3.84 (m, 2H), 3.65 (sep, J=6.1 Hz, 1H),1.11 (d, J=6.1 Hz, 6H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-75-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridine(Reference Compound 5-7)

The reaction was performed by the method described in Reference Example5-1, except that 5-bromo-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine wasreplaced by5-bromo-3-fluoro-2-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridinesynthesized in the same manner as in Reference Example 9. Consequently,the title compound (quantitative yield) was obtained as light yellowoil.

¹H-NMR spectrum (400 MHz, CDCl₃) δ: 8.15-8.08 (m, 1H), 7.51-7.43 (m,1H), 7.43-7.35 (m, 1H), 7.31-7.23 (m, 1H), 7.23-7.14 (m, 1H), 4.88-4.82(m, 2H), 4.76-4.65 (m, 2H), 4.48-4.38 (m, 2H), 4.21-4.07 (m, 2H),3.96-3.82 (m, 1H), 3.61-3.48 (m, 1H), 1.94-1.42 (m, 6H), 0.96 (s, 9H),0.13 (s, 6H).

Reference Example 5-82-(Azetidin-1-yl)-5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoropyridine(Reference Compound 5-8)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by2-(azetidin-1-yl)-5-bromo-3-fluoropyridine synthesized in the samemanner as in Reference Example 10-1. Consequently, the title compound(yield 71%) was obtained as a white solid.

Mass spectrum (ESI, m/z): 391[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.07 (m, 1H), 7.67-7.58 (m,1H), 7.50-7.39 (m, 2H), 7.31-7.23 (m, 1H), 4.80 (s, 2H), 4.22-4.06 (m,4H), 2.43-2.24 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-95-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-fluoroazetidin-1-yl)pyridine(Reference Compound 5-9)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-3-fluoro-2-(3-fluoroazetidin-1-yl)pyridine synthesized in thesame manner as in Reference Example 11-1. Consequently, the titlecompound (yield 63%) was obtained as light yellow oil. Mass spectrum(ESI, m/z): 409[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.17-8.11 (m, 1H), 7.72-7.66 (m,1H), 7.50-7.40 (m, 2H), 7.33-7.25 (m, 1H), 5.71-5.38 (m, 1H), 4.81 (s,2H), 4.56-4.37 (m, 2H), 4.27-4.11 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-105-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridine(Reference Compound 5-10)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridine synthesized inthe same manner as in Reference Example 11-2. Consequently, the titlecompound (yield 75%) was obtained as light yellow oil.

Reference Example 5-115-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methylazetidin-1-yl)pyridine(Reference Compound 5-11)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-3-fluoro-2-(3-methylazetidin-1-yl)pyridine synthesized in thesame manner as in Reference Example 10-2. Consequently, the titlecompound (yield 86%) was obtained as light yellow oil. Mass spectrum(ESI, m/z): 405[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₄) δ: 8.12-8.08 (m, 1H), 7.65-7.58 (m,1H), 7.48-7.39 (m, 2H), 7.31-7.24 (m, 1H), 4.80 (s, 2H), 4.28-4.20 (m,2H), 3.74-3.67 (m, 2H), 2.88-2.77 (m, 1H), 1.25 (d, J=6.8 Hz, 3H), 0.91(s, 9H), 0.11 (s, 6H).

Reference Example 5-125-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-3-fluoropyridine(Reference Compound 5-12)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-2-(3,3-dimethylazetidin-1-yl)-3-fluoropyridine synthesized inthe same manner as in Reference Example 10-3. Consequently, the titlecompound (yield 75%) was obtained as light yellow oil.

Mass spectrum (ESI, m/z): 419[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.06 (m, 1H), 7.65-7.56 (m,1H), 7.48-7.38 (m, 2H), 7.34-7.22 (m, 1H), 4.80 (s, 2H), 3.85-3.79 (m,4H), 1.30 (s, 6H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-135-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridine(Reference Compound 5-13)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by5-bromo-3-fluoro-2-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridinesynthesized in the same manner as in Reference Example 14. Consequently,the title compound (yield 90%) was obtained as light yellow oil.

Mass spectrum (ESI, m/z): 505[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₎ δ: 8.17-8.07 (m, 1H), 7.70-7.60 (m,1H), 7.51-7.39 (m, 2H), 7.33-7.22 (m, 1H), 4.87-4.83 (m, 1H), 4.80 (s,2H), 4.20-4.07 (m, 2H), 4.01-3.91 (m, 2H), 3.89-3.80 (m, 1H), 3.50-3.40(m, 1H), 1.89-1.27 (m, 9H), 0.91 (s, 9H), 0.11 (s, 6H).

Reference Example 5-146-[5-(3-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoropyridin-2-yl]-2-oxa-6-azaspiro[3.3]heptane(Reference Compound 5-14)

The reaction was performed by the method described in Reference Example5-2, except that5-bromo-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridine was replaced by6-(5-bromo-3-fluoropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptanesynthesized in the same manner as in Reference Example 10-4.Consequently, the title compound (yield 71%) was obtained as lightyellow oil.

Mass spectrum (ESI, m/z): 433[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.09 (m, 1H), 7.68-7.61 (m,1H), 7.48-7.40 (m, 2H), 7.31-7.24 (m, 1H), 4.80 (s, 2H), 4.73 (s, 4H),4.32-4.26 (m, 4H), 0.91 (s, 9H), 0.10 (s, 6H).

Reference Example 6-1{2-Fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol(Reference Compound 6-1)

1 M tetrabutylammonium fluoride/THF solution 1.2 mL (1.2 mmol) was addedto a THF (8 mL) solution of5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine399 mg (0.949 mmol) synthesized in the same manner as in ReferenceExample 5-1, and the mixture was stirred at room temperature for 2hours. After the completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography (eluting solvent;hexane:ethyl acetate) to give the title compound 280 mg (0.914 mmol,yield 96%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.08 (m, 1H), 7.70-7.62 (m,1H), 7.50-7.37 (m, 2H), 7.30-7.22 (m, 1H), 5.32 (t, J=5.7 Hz, 1H), 4.60(d, J=5.7 Hz, 2H), 4.39-4.24 (m, 3H), 3.98-3.89 (m, 2H), 3.26 (s, 3H).

Reference Example 6-2(2-Fluoro-3-{5-fluoro-6-[3-(methoxy-d₃)azetidin-1-yl]pyridin-3-yl}phenyl)methanol(Reference Compound 6-2)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-[3-(methoxy-d₃)azetidin-1-yl]pyridinesynthesized in the same manner as in Reference Example 5-2.Consequently, the title compound (yield 91%) was obtained as a whitesolid.

Mass spectrum (ESI, m/z): 310[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.15-8.08 (m, 1H), 7.71-7.60 (m,1H), 7.49-7.38 (m, 2H), 7.30-7.21 (m, 1H), 5.32 (t, J=4.8 Hz, 1H), 4.60(d, J=4.8 Hz, 2H), 4.40-4.24 (m, 3H), 3.99-3.87 (m, 2H).

Reference Example 6-3{3-[6-(3-Ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol(Reference Compound 6-3)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3-ethoxyazetidin-1-yl)-3-fluoropyridinesynthesized in the same manner as in Reference Example 5-3.Consequently, the title compound (yield 94%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 321[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.13-8.09 (m, 1H), 7.70-7.62 (m,1H), 7.50-7.37 (m, 2H), 7.29-7.22 (m, 1H), 5.33 (br s, 1H), 4.60 (br s,2H), 4.47-4.39 (m, 1H), 4.37-4.28 (m, 2H), 3.98-3.85 (m, 2H), 3.46 (q,J=7.0 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H).

Reference Example 6-4(2-Fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}phenyl)methanol(Reference Compound 6-4)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-[3-(2-fluoroethoxy)azetidin-1-yl]pyridinesynthesized in the same manner as in Reference Example 5-4.Consequently, the title compound (yield 94%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 339[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d) δ: 8.13-8.11 (m, 1H), 7.70-7.62 (m,1H), 7.51-7.38 (m, 2H), 7.31-7.22 (m, 1H), 5.34 (t, J=5.3 Hz, 1H),4.66-4.56 (m, 3H), 4.55-4.47 (m, 2H), 4.38-4.29 (m, 2H), 3.99-3.91 (m,2H), 3.76-3.61 (m, 2H).

Reference Example 6-5{2-Fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol(Reference Compound 6-5)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-propoxyazetidin-1-yl)pyridinesynthesized in the same manner as in Reference Example 5-5.Consequently, the title compound (yield 94%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 335[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.09 (m, 1H), 7.70-7.61 (m,1H), 7.51-7.37 (m, 2H), 7.31-7.21 (m, 1H), 5.38-5.29 (m, 1H), 4.59 (brs, 2H), 4.46-4.39 (m, 1H), 4.36-4.28 (m, 2H), 3.96-3.87 (m, 2H),3.41-3.29 (m, 2H), 1.54 (sext, J=7.3 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H).

Reference Example 6-6{2-Fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]phenyl}methanol(Reference Compound 6-6)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-isopropoxyazetidin-1-yl)pyridinesynthesized in the same manner as in Reference Example 5-6.Consequently, the title compound (yield 82%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 335[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.08 (m, 1H), 7.70-7.60 (m,1H), 7.48-7.39 (m, 2H), 7.30-7.20 (m, 1H), 5.33 (br s, 1H), 4.63-4.57(m, 2H), 4.56-4.48 (m, 1H), 4.37-4.30 (m, 2H), 3.95-3.85 (m, 2H), 3.65(sep, J=6.1 Hz, 1H), 1.11 (d, J=6.1 Hz, 6H).

Reference Example 6-7[2-Fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)phenyl]methanol(Reference Compound 6-7)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridinesynthesized in the same manner as in Reference Example 5-7.Consequently, the title compound (yield 94%) was obtained as lightyellow oil.

¹H-NMR spectrum (400 MHz, CDCl₃) δ: 8.14-8.09 (m, 1H), 7.45-7.37 (m,2H), 7.35-7.29 (m, 1H), 7.23-7.17 (m, 1H), 4.86-4.79 (m, 2H), 4.78-4.65(m, 2H), 4.50-4.35 (m, 2H), 4.25-4.05 (m, 2H), 3.94-3.85 (m, 1H),3.60-3.51 (m, 1H), 1.91-1.50 (m, 6H).

Reference Example 6-8{3-[6-(Azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol(Reference Compound 6-8)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by2-(azetidin-1-yl)-5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoropyridinesynthesized in the same manner as in Reference Example 5-8.Consequently, the title compound (yield 88%) was obtained as a whitesolid.

Mass spectrum (ESI, m/z): 277[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.07 (m, 1H), 7.66-7.58 (m,1H), 7.49-7.38 (m, 2H), 7.30-7.21 (m, 1H), 5.30 (br s, 1H), 4.59 (br s,2H), 4.25-3.99 (m, 4H), 2.45-2.28 (m, 2H).

Reference Example 6-9{2-Fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]phenyl}methanol(Reference Compound 6-9)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-fluoroazetidin-1-yl)pyridinesynthesized in the same manner as in Reference Example 5-9.Consequently, the title compound (yield 84%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 295[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.16-8.11 (m, 1H), 7.75-7.65 (m,1H), 7.52-7.38 (m, 2H), 7.30-7.19 (m, 1H), 5.67-5.41 (m, 1H), 5.32 (brs, 1H), 4.63-4.57 (m, 2H), 4.53-4.39 (m, 2H), 4.25-4.10 (m, 2H).

Reference Example 6-10{3-[6-(3,3-Difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol(Reference Compound 6-10)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridinesynthesized in the same manner as in Reference Example 5-10.Consequently, the title compound (yield 83%) was obtained as a whitesolid.

Mass spectrum (ESI, m/z): 313[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₎ δ: 8.22-8.15 (m, 1H), 7.82-7.73 (m,1H), 7.53-7.39 (m, 2H), 7.32-7.23 (m, 1H), 5.34 (br s, 1H), 4.64-4.50(m, 6H).

Reference Example 6-11(2-Fluoro-3-(5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl)phenyl)methanol(Reference Compound 6-11)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methylazetidin-1-yl)pyridinesynthesized in the same manner as in Reference Example 5-11.Consequently, the title compound (yield 94%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 291[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d) δ: 8.13-8.04 (m, 1H), 7.66-7.56 (m,1H), 7.48-7.36 (m, 2H), 7.29-7.21 (m, 1H), 5.31 (br s, 1H), 4.59 (br s,2H), 4.31-4.18 (m, 2H), 3.74-3.65 (m, 2H), 2.90-2.75 (m, 1H), 1.25 (d,J=6.9 Hz, 3H).

Reference Example 6-12{3-[6-(3,3-Dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorophenyl}methanol(Reference Compound 6-12)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-3-fluoropyridinesynthesized in the same manner as in Reference Example 5-12.Consequently, the title compound (quantitative yield) was obtained ascolorless oil.

Mass spectrum (ESI, m/z): 305[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₎ δ: 8.12-8.06 (m, 1H), 7.67-7.57 (m,1H), 7.50-7.36 (m, 2H), 7.29-7.21 (m, 1H), 5.31 (br s, 1H), 4.59 (br s,2H), 3.85-3.77 (m, 4H), 1.30 (s, 6H).

Reference Example 6-13[2-Fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)phenyl]methanol(Reference Compound 6-13)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridinesynthesized in the same manner as in Reference Example 5-13.Consequently, the title compound (yield 85%) was obtained as colorlessoil.

Reference Example 6-14{2-Fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]phenyl}methanol(Reference Compound 6-14)

The reaction was performed by the method described in Reference Example6-1, except that5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridinewas replaced by6-[5-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-2-fluorophenyl)-3-fluoropyridin-2-yl]-2-oxa-6-azaspiro[3.3]heptanesynthesized in the same manner as in Reference Example 5-14.Consequently, the title compound (yield 94%) was obtained as colorlessoil.

Mass spectrum (ESI, m/z): 319[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.14-8.09 (m, 1H), 7.68-7.61 (m,1H), 7.49-7.36 (m, 2H), 7.30-7.22 (m, 1H), 5.41-5.23 (m, 1H), 4.73 (s,4H), 4.63-4.51 (m, 2H), 4.33-4.23 (m, 4H).

Reference Example 7 2-Fluoroethyl methanesulfonate (Reference Compound7)

At 0° C., triethylamine 1.81 mL (13.0 mmol) was added to a methylenechloride (5 mL) solution of 2-fluoromethanol 0.500 mL (8.66 mmol). Next,a solution of methanesulfonyl chloride 0.740 mL (9.56 mmol) in methylenechloride 5 mL was added thereto dropwise at 0° C. The mixture wasstirred for 1 hour and was stirred at room temperature for 2 hours.After the completion of the reaction, water was added to the reactionmixture and followed by extraction with methylene chloride. The organiclayer was washed with water, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theconcentrated residue was dried under reduced pressure to give a crudeproduct 1.25 g including the title compound as yellow oil.

Reference Example 8 5-Bromo-3-fluoro-2-(3-methoxyazetidin-1-yl)pyridine(Reference Compound 8)

Silver oxide 2.81 g (12.1 mmol) and 2-iodopropane 2.02 mL (20.2 mmol)were added to an acetonitrile (10 mL) solution of1-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-ol 1.00 g (4.05 mmol)synthesized in the same manner as in Reference Example 1, and themixture was stirred at room temperature for 4 days. After the completionof the reaction, the reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography (eluting solvent;hexane:ethyl acetate) to give the title compound 583 mg (2.02 mmol,yield 50%) as colorless oil.

Mass spectrum (ESI, m/z): 289, 291 [M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-8.00 (m, 1H), 7.82-7.76 (m,1H), 4.52-4.46 (m, 1H), 4.31-4.24 (m, 2H), 3.85-3.80 (m, 2H), 3.63 (sep,J=6.1 Hz, 1H), 1.10 (d, J=6.1 Hz, 6H).

Reference Example 95-Bromo-3-fluoro-2-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridine(Reference Compound 9)

3,4-dihydro-2H-pyran 0.18 mL (1.99 mmol) and pyridiniump-toluenesulfonate 61 mg (0.243 mmol) were added to a methylene chloride(8 mL) solution of 1-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-ol 300 mg(1.21 mmol) synthesized in the same manner as in Reference Example 1,and the mixture was stirred at room temperature for 16 hours. After thecompletion of the reaction, a saturated aqueous sodium bicarbonatesolution was added to the reaction mixture, and followed by extractionwith methylene chloride. The organic layer was washed with brine, driedover anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography (eluting solvent;hexane:ethyl acetate) to give the title compound 310 mg (0.936 mmol,yield 77%) as colorless oil.

¹H-NMR spectrum (400 MHz, CDCl₃) δ: 7.99-7.95 (m, 1H), 7.32-7.27 (m,1H), 4.73-4.63 (m, 2H), 4.41-4.30 (m, 2H), 4.16-4.00 (m, 2H), 3.92-3.83(m, 1H), 3.59-3.48 (m, 1H), 1.96-1.42 (m, 6H).

Reference Example 10-1 2-(Azetidin-1-yl)-5-bromo-3-fluoropyridine(Reference Compound 10-1)

Azetidine hydrochloride 289 mg (3.09 mmol) and triethylamine 0.90 mL(6.46 mmol) were added to an ethanol (6 mL) solution of5-bromo-2,3-difluoropyridine 300 mg (1.55 mmol), and the mixture wasstirred at 50° C. for 2 hours. After the completion of the reaction,water was added to the reaction mixture, and followed by extraction withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The concentrated residue was purified by silicagel column chromatography (eluting solvent; hexane:ethyl acetate) togive the title compound 342 mg (1.48 mmol, yield 96%) as a white solid.

Mass spectrum (ESI, m/z): 231, 233[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₎ δ: 8.02-7.98 (m, 1H), 7.79-7.72 (m,1H), 4.18-3.96 (m, 4H), 2.44-2.23 (m, 2H).

Reference Example 10-25-Bromo-3-fluoro-2-(3-methylazetidin-1-yl)pyridine (Reference Compound10-2)

The reaction was performed by the method described in Reference Example10-1, except that the azetidine hydrochloride was replaced by3-methylazetidine hydrochloride. Consequently, the title compound(quantitative yield) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 245, 247[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.03-7.97 (m, 1H), 7.80-7.71 (m,1H), 4.23-4.11 (m, 2H), 3.67-3.60 (m, 2H), 2.86-2.74 (m, 1H), 1.22 (d,J=6.9 Hz, 3H).

Reference Example 10-35-Bromo-2-(3,3-dimethylazetidin-1-yl)-3-fluoropyridine (ReferenceCompound 10-3)

The reaction was performed by the method described in Reference Example10-1, except that the azetidine hydrochloride was replaced by3,3-dimethylazetidine hydrochloride. Consequently, the title compound(quantitative yield) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 259, 261[M+1]+.

Reference Example 10-46-(5-Bromo-3-fluoropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (ReferenceCompound 10-4)

The reaction was performed by the method described in Reference Example10-1, except that the azetidine hydrochloride was replaced by2-oxa-6-azaspiro[3,3]heptane oxalate. Consequently, the title compound(yield 47%) was obtained as a white solid.

Mass spectrum (ESI, m/z): 273, 275[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-8.00 (m, 1H), 7.83-7.76 (m,1H), 4.71 (s, 4H), 4.26-4.20 (m, 4H).

Reference Example 11-15-Bromo-3-fluoro-2-(3-fluoroazetidin-1-yl)pyridine (Reference Compound11-1)

3-Fluoroazetidine hydrochloride 230 mg (2.06 mmol) and cesium carbonateweighing 1.0 g (3.07 mmol) were added to an N-methylpyrrolidone (6 mL)solution of 5-bromo-2,3-difluoropyridine 200 mg (1.03 mmol), and themixture was stirred at 80° C. for 2 hours. After the completion of thereaction, water was added to the reaction mixture, and followed byextraction with ethyl acetate. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography (eluting solvent;hexane:ethyl acetate) to give the title compound 252 mg (1.01 mmol,yield 98%) as colorless oil.

Mass spectrum (ESI, m/z): 249, 251 [M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.08-8.04 (m, 1H), 7.88-7.81 (m,1H), 5.67-5.33 (m, 1H), 4.51-4.28 (m, 2H), 4.22-3.95 (m, 2H).

Reference Example 11-25-Bromo-2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridine (ReferenceCompound 11-2)

The reaction was performed by the method described in Reference Example11-1, except that the 3-fluoroazetidine hydrochloride was replaced by3,3-difluoroazetidine hydrochloride. Consequently, the title compound(yield 78%) was obtained as colorless oil.

Mass spectrum (ESI, m/z): 267, 269[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d) δ: 8.15-8.08 (m, 1H), 7.99-7.90 (m,1H), 4.62-4.37 (m, 4H).

Reference Example 12 1-(5-Bromo-3-fluoropyridin-2-yl)azetidin-3-one(Reference Compound 12)

Azadol 40 mg (0.261 mmol) and iodobenzene diacetate 1.80 g (5.59 mmol)were added to a methylene chloride (10 mL) solution of1-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-ol 1.00 g (4.05 mmol)synthesized in the same manner as in Reference Example 1, and themixture was stirred at room temperature for 22 hours. After thecompletion of the reaction, a saturated aqueous sodium bicarbonatesolution and sodium thiosulfate were added to the reaction mixture, andthe mixture was stirred for 1 hour and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous sodium bicarbonatesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. TBME and hexane wereadded to the concentrated residue, and the mixture was stirred at roomtemperature. The solid was collected by filtration to give the titlecompound 504 mg (2.06 mmol, yield 51%) as a white solid.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.16-8.12 (m, 1H), 7.99-7.90 (m,1H), 4.95-4.91 (m, 4H).

Reference Example 131-(5-Bromo-3-fluoropyridin-2-yl)-3-methylazetidin-3-ol (ReferenceCompound 13)

At 0° C., 1 M methyl magnesium bromide THF solution 4.90 mL (4.90 mmol)was added dropwise to a THF (10 mL) solution of1-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-one 1.0 g (4.08 mmol)synthesized in the same manner as in Reference Example 12, and themixture was stirred at room temperature for 1 hour. After the completionof the reaction, saturated aqueous ammonium chloride solution was addedto the reaction mixture, and followed by extraction with ethyl acetate.The organic layer was washed with water, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The concentrated residue was purified by silica gel columnchromatography (eluting solvent; hexane:ethyl acetate) to give the titlecompound 990 mg (3.79 mmol, yield 93%) as colorless oil.

Mass spectrum (ESI, m/z): 261, 263[M+1]⁺.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.04-8.00 (m, 1H), 7.81-7.76 (m,1H), 5.61 (br s, 1H), 3.94-3.87 (m, 4H), 1.44 (s, 3H).

Reference Example 145-Bromo-3-fluoro-2-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridine(Reference Compound 14)

3,4-dihydro-2H-pyran 0.2 mL (2.21 mmol) and pyridiniump-toluenesulfonate 33 mg (0.131 mmol) were added to a THF (6 mL)solution of 1-(5-bromo-3-fluoropyridin-2-yl)-3-methylazetidin-3-ol 340mg (1.30 mmol) synthesized in the same manner as in Reference Example13, and the mixture was stirred at 50° C. for 7 hours. After thecompletion of the reaction, water was added to the reaction mixture, andfollowed by extraction with ethyl acetate. The organic layer was washedwith water, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure. The concentratedresidue was purified by silica gel column chromatography (elutingsolvent; hexane:ethyl acetate) to give the title compound 396 mg (1.15mmol, yield 88%) as colorless oil.

Mass spectrum (ESI, m/z): 345, 347[M+l]+.

¹H-NMR spectrum (400 MHz, DMSO-d₆) δ: 8.05-8.00 (m, 1H), 7.84-7.76 (m,1H), 4.95-4.76 (m, 1H), 4.14-4.00 (m, 2H), 3.96-3.78 (m, 3H), 3.48-3.40(m, 1H), 1.89-1.26 (m, 9H).

Test Example 1 Human VAP-1 Enzyme Inhibition Test

This test was conducted by modifying the method of P. H. Yu et al.(Diabetologia 40 1243 (1997)). Human VAP-1 enzyme (R&D Systems, Inc.)was pre-incubated in a 96-well plate with the compound dissolved indimethylsulfoxide at room temperature for 20 minutes. Next, in asolution to the final volume of 200 μL, the enzyme reaction solution wasincubated with ¹⁴C-benzylamine (final concentration 100 μM) at 37° C.for 1 hour. The reaction was terminated by the addition of 100 μL of 2 Mcitric acid solution to the reaction solution. The oxidative product wasextracted using a toluene/ethyl acetate mixture and the radioactivitywas measured with a liquid scintillation counter. The inhibition ratioof the compound was calculated using the following equation.Inhibition ratio=(1−[VAP-1 enzyme activity after treatment with thecompound]/[VAP-1 enzyme activity in the presence of dimethylsulfoxidealone without the compound])×100  [Math. 1]

In this test, the compounds of the present invention showed excellenthuman VAP-1 inhibitory activity. For example, inhibition ratio of 50% orover was attained by the compounds, each 30 nM, of Examples 1, 2, 3, 4,6, 8, 9, 10, 11, 12, 13, 15 and 16.

Test Example 2 Human Plasma VAP-1 Inhibition Test

This test was conducted by modifying the method of P. H. Yu et al.(Diabetologia 40 1243 (1997)). Human blood was collected from a healthydonor in a heparin tube, and was centrifuged at 3000 rpm and 4° C. for10 minutes to get plasma. The plasma was pre-incubated in a 96-wellmicroplate with the compound dissolved in dimethylsulfoxide andPargyline (final concentration 100 μM) at room temperature for 20minutes. Next, in a solution to the final volume of 200 μL, the plasmareaction solution was incubated with ¹⁴C-benzylamine (finalconcentration 50 μM) at 37° C. for 1 hour. The reaction was terminatedby the addition of 100 μL of 2 M citric acid solution to the reactionsolution. The oxidative product was extracted using a toluene/ethylacetate mixture and the radioactivity was measured with a liquidscintillation counter. The inhibition ratio of the compound wascalculated using the following equation.Inhibition ratio=(1−[VAP-1 activity after treatment with thecompound]/[VAP-1 activity in the presence of dimethylsulfoxide alonewithout the compound])×100  [Math. 2]

Test Example 3 Rat Plasma VAP-1 Inhibition Test

This test was conducted by modifying the method of P. H. Yu et al.(Diabetologia 40 1243 (1997)). Blood was collected from 7-12 week old SDmale rats in heparin tubes, and was centrifuged at 3000 rpm and 4° C.for 10 minutes to get plasma. The plasma was pre-incubated in a 96-wellmicroplate with the compound dissolved in dimethylsulfoxide andPargyline (final concentration 100 μM) at room temperature for 20minutes. Next, in a solution to the final volume of 200 μL, the plasmareaction solution was incubated with ¹⁴C-benzylamine (finalconcentration 2.5 μM) at 37° C. for 3 hours. The reaction was terminatedby the addition of 100 μL of 2 M citric acid solution to the reactionsolution. The oxidative product was extracted using a toluene/ethylacetate mixture and the radioactivity was measured with a liquidscintillation counter. The inhibition ratio of the compound wascalculated using the following equation.Inhibition ratio={1−[VAP-1 activity after treatment with thecompound]/[VAP-1 activity in the presence of dimethylsulfoxide alonewithout the compound]}×100  [Math. 3]

Test Example 4 (Ex Vivo) Rat Plasma VAP-1 Inhibition Test after OralAdministration of the Compound

The compound was orally administered (0.3-10 mg/kg) to 7-12 week old SDmale rats in the non-fasting state. Under anesthesia, the blood wascollected in heparin tubes from the jugular vein before theadministration and 3, 8 and 24 hours after the administration. The bloodwas centrifuged at 14000 rpm for 10 minutes to get plasma. The VAP-1enzyme activity in the plasma was measured by radiochemical enzymeassay.

The radiochemical enzyme assay was conducted by modifying the method ofP. H. Yu et al. (Diabetologia 40 1243 (1997)). ¹⁴C-benzylamine (2.5 μM)was added to the obtained plasma, and was incubated at 37° C. for 3hours. The reaction was terminated by the addition of 100 μL of 2 Mcitric acid solution to the reaction solution. The oxidative product wasextracted using a toluene/ethyl acetate mixture and the radioactivitywas measured with a liquid scintillation counter. The inhibition ratioof the compound was calculated using the following equation.Inhibition ratio=(1−[Plasma VAP-1 activity after administration of thecompound]/[Plasma VAP-1 activity before administration])×100  [Math. 4]

In this test, the compounds of the present invention showed excellentVAP-1 inhibitory activity. For example, inhibition ratio of 50% or overwas attained 3 hours after the administration of the compounds, each ata dose of 0.3 mg/kg, of Examples 1, 2, 3, 4, 6, 8, 9, 10, 11, 12, 13, 15and 16.

Test Example 5 Effect on Albuminuria of Diabetic Rats

Diabetes is induced by intravenous injection of 50 mg/ml/kgstreptozotocin (STZ) in 2 mM citric acid buffer solution (pH 4.5) into 7to 8 week old (weighing 180 to 250 g) SD rats. At the same time, normalrats are injected with the same amount of 2 mM citric acid buffersolution (pH 4.5) as control. The blood glucose level is measured by anenzyme electrode method. On the fourth day after the STZ injection, ratswith a blood glucose level above 350 mg/dL are classified as a diabeticmodel. The compound is administered daily for 4 weeks from the day ofthe STZ injection. After the treatment with the compound for 4 weeks,urine is collected for 24 hours using a metabolic cage, and the albuminconcentration in the urine is measured.

Test Example 6 Effect on Livers in Non-Alcoholic Steatohepatitis (NASH)Models

This study is conducted using NASH model mice/STAM (registeredtrademark) model mice (Medical Molecular Morphology, 46, 141 (2013))from Stelic Institute & Co., Inc.

Fourteen-day-pregnant C57BL6J/JcL mice (CLEA Japan, Inc.) are fed andallowed to give the birth. Two-day-old mice are subcutaneously injectedwith streptozotocin (SIGMA-ALDRICH JAPAN) in physiological saline(Japanese Pharmacopoeia, Otsuka Pharmaceutical Co., Ltd.) one time totheir backs. After 4 weeks of age, the mice are fed with high fat diet(High Fat Diet 32 (sterilized by radiation, CLEA Japan, Inc.) until theend of the experimental.

The compound is orally administered daily from 5- or 6-week-old. At 9-or 11-week-old, the animals are sacrificed under anesthesia. The liversare collected and their wet weights are measured. Paraffin sections orfrozen sections are prepared from part of the livers, and arehistopathologically examined, and the NAFLD activity score is measured.Further, RNA is extracted from the part of the livers, and theexpression of fibrosis marker gene is measured by a quantitative PCRmethod. The results are statistically analyzed using EXSUS or Prism 4(manufactured by GraphPad Software).

Test Example 7 Cytotoxicity Inhibition Test in Human Normal GlomerularMicrovascular Endothelial Cells

Human normal glomerular microvascular endothelial cells are plated at6000 cells/well in a collagen-coated 96-well culture plate. After oneday of culture, the medium at each well is completely removed byaspiration and replaced with 50 μL of the compound solution diluted withthe basal medium. The basal medium containing 0.1% DMSO is added tocontrol wells. Subsequently, the plate is incubated in CO₂ incubator for30 minutes. Fifty microliters of 2 mM methylamine diluted with the basalmedium is added (final concentration 1 mM) to each negative control well(0% inhibition) as well as the compound-containing well, and 50 μL ofthe basal medium is added to each positive control well (100%inhibition). The plate is incubated in CO₂ incubator for 2 days. Tenmicroliters of CCK-8 is added to each well and the mixtures areincubated in a plate incubator at 37° C. for approximately 2 hours afterstirring with a plate shaker. The absorbance of the mixtures at 450 nmis measured with a multiplate reader. The cytotoxicity inhibition ratioof the compound is calculated from the following equation.Inhibition ratio={[Average absorbance of the compound-containingwells]−[Average absorbance of negative control wells]}/{[Averageabsorbance of positive control wells]−[Average absorbance of negativecontrol wells]}×100  [Math. 5]

Test Example 8 Cytotoxicity Inhibition Test in Human Normal HepaticSinusoid-Like Microvascular Endothelial Cells

Human normal hepatic sinusoid-like microvascular endothelial cells areplated at 6000 cells/well in a collagen-coated 96-well culture plate.After one day of culture, the medium at each well is completely removedby aspiration and replaced with 50 μL of the compound solution dilutedwith the basal medium. The basal medium containing 0.1% DMSO is added tocontrol wells. Subsequently, the plate is incubated in CO₂ incubator for30 minutes. Fifty microliters of 2 mM methylamine diluted with the basalmedium is added (final concentration 1 mM) to each negative control well(0% inhibition) as well as the compound-containing well, and 50 μL ofthe basal medium is added to each positive control well (100%inhibition). The plate is incubated in CO₂ incubator for 2 days. Tenmicroliters of CCK-8 is added to each well and the mixtures areincubated in a plate incubator at 37° C. for approximately 2 hours afterstirring with a plate shaker. The absorbance of the mixtures at 450 nmis measured with a multiplate reader. The cytotoxicity inhibition ratioof the compound is calculated from the following equation.Inhibition ratio=([Average absorbance of the compound-containingwells]−[Average absorbance of negative control wells])/([Averageabsorbance of positive control wells]−[Average absorbance of negativecontrol wells])×100  [Math. 6]

Test Example 9 Rat Pharmacokinetic (PK) Study (Concentration of Compoundin Plasma after Oral Administration)

Seven to eight week old SD rats (weighing 180 to 250 g) were orallyadministered with a suspension of the compound in 0.5 W/V %methylcellulose 400 solution. Under anesthesia, the blood was collectedfrom the jugular vein in EDTA tubes at 0.25, 0.5, 1, 2, 4, 6, 8 and 24hours after the administration of the compound. The blood wascentrifuged at 4° C. and 6000 g for 3 minutes to give plasma.Acetonitrile was added to the plasma, and the mixture was stirred with ashaker at 750 rpm for 3 minutes and was deproteinized by centrifugationat 3700 rpm for 2 minutes. The obtained sample was analyzed by LC/MSunder the following conditions.

The concentration of the compound in the plasma at each blood samplingtime was determined by an internal standard method, and AUC all (AreaUnder Curve) was calculated by a trapezoidal method.

The following LC and MS systems were used for measurement.

LC: CBM 30 series manufactured by Shimadzu Corporation

Column: Phenomenex Kinetex C18 (50×2.1 mm, 2.6 μm)

Column temperature: 40° C.

Flow rate: 0.3 mL/min

Mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: 0.1%formic acid, 50% acetonitrile/methanol mixture

Gradients: 0-2 min: A/B=90/10-10/90, 2-3 min: A/B=10/90, 3-3.01 min:A/B=10/90-90/10

MS: 3200 manufactured by SCIEX

Ionization: ESI

Mode: positive

In this study, the compounds of the present invention showed excellentPK. For example, 1000 ng-h/mL or higher AUC was attained by thecompounds of Examples 8, 15 and 16 at a dose of 3 mg/kg, and the amountof metabolites found in the blood was small.

Test Example 10 Cytochrome P450 (CYP) Metabolism Test

The reaction solution for metabolic stability measurement was preparedby mixing 2 mg protein/mL human recombinant CYP enzyme 3A4, 2D6, 2C9,2C19, 1A2 or 2C8, 1 mg/mL glucose 6-phosphate (G-6-P) as a cofactor, 0.4unit/mL glucose-6-phosphate dehydrogenase (G-6-P-DH), 0.665 mg/mLmagnesium chloride (MgCl₂) and 1 mg/mL nicotinamide adenine dinucleotide(NADP+Na) into 1 mL of 100 mmol/L potassium phosphate buffer (pH 7.4) sothat the final concentrations would be the concentrations describedabove. The human recombinant CYP enzyme used herein was obtained fromCypex Ltd. (UK) via Nosan Co., Ltd.

The reaction solution was pre-incubated at 37° C. for 5 minutes, and thereaction was initiated by adding the compound in a final concentrationof 5 μmol/L. 100 Microliter portions were collected from the reactionsystem at 0, 5, 10, 15, 20 and 30 minutes after the start of metabolicreaction, and the reaction was terminated by adding the portion to 300μL methanol. After the completion of the reaction, the sample wassubjected to post treatments such as deproteinization and analyzed byUV-HPLC as described below.

Analysis Method

The peak area of the compound was calculated using Lab Solution Software(Shimadzu Corporation), and the residual ratio (%) of the compound ateach incubation time was determined using the following equation.Residual ratio (%)=[Peak area at incubation time]/[Peak area at 0minutes]×100  [Math. 7]

Next, the residual amount (nmol/mL) of the compound at each incubationtime was determined using the following equation.Residual amount (nmol/mL)=[Initial concentration in reaction solution (5nmol/mL)]×residual ratio/100  [Math. 8]

Lastly, a graph was drawn on Excel which plotted the reaction time onthe abscissa and the residual amount on the ordinate, and the slope inthe time range in which linearity was observed was determined as theelimination rate (nmol/min/200 μmol-CYP).

The LC system used is as follows.

LC: LC20 HPLC system manufactured by Shimadzu Corporation

Column: Phenomenex Kinetex C18 (100×2.1 mm, 2.6 μm)

Column temperature: 40° C.

Flow rate: 0.25 mL/min

Mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: 0.1%formic acid, 50% acetonitrile/methanol mixture

Gradients: 0-3 min: A/B=90/10, 3-11 min: 90/10-5/95, 11-15 min:A/B=5/95, 15-15.1 min: A/B=5/95-90/10

Measurement UV wavelengths: 200 to 350 nm

In this study, the compounds of the invention showed excellent metabolicstability. For example, the compounds of Examples 8, 15 and 16 attainedan elimination rate of not more than 0.030 nmol/min/200 pmol-CYP withall kinds of CYP.

INDUSTRIAL APPLICABILITY

The compounds of the present invention of the general formula (I) orpharmacologically acceptable salts thereof have high VAP-1 inhibitoryactivity and excellent pharmacokinetic characteristics, and aretherefore useful for the treatment of diseases that are prevented,alleviated and/or remedied by inhibiting VAP-1, typically, nonalcoholicfatty liver diseases such as nonalcoholic steatohepatitis; inflammatorydiseases such as atopic dermatitis and psoriasis; diabetic complicationssuch as diabetic neuropathy, diabetic retinopathy (in particular,diabetic macular edema) and diabetic nephropathy; vascular diseases suchas atherosclerosis: heart diseases such as myocardial infarction; andmetabolic disorders such as obesity.

The invention claimed is:
 1. A compound of formula (I):

wherein, X is a CR1R2, R1 and R2, independently of each other, are ahydrogen atom, halogen atom, hydroxy group, optionally substituted C1-C6alkyl group or optionally substituted C1-C6 alkoxy group, where the term“substituted” refers to being substituted with at least one substituentselected from the group consisting of a deuterium atom, halogen atom,hydroxy group and C1-C6 alkoxy group, or a pharmacologically acceptablesalt thereof.
 2. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein R1 is a hydrogenatom, halogen atom, hydroxy group, optionally substituted C1-C6 alkylgroup or optionally substituted C1-C6 alkoxy group, and R2 is a hydrogenatom, halogen atom or C1-C3 alkyl group.
 3. The compound according toclaim 2 or a pharmacologically acceptable salt thereof, wherein R1 is ahalogen atom, hydroxy group, C1-C6 alkoxy group or C1-C6 alkoxy groupsubstituted with at least one deuterium atom.
 4. A compound or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,2-fluoro-3-{5-fluoro-6-[3-(methoxy-d3)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate,3-[6-(3-ethoxyazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate,2-fluoro-3-{5-fluoro-6-[3-(2-fluoroethoxy)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-propoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-isopropoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,2-fluoro-3-(5-fluoro-6-{3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,3-[6-(azetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,3-[6-(3,3-difluoroazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluoro-benzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate,3-[6-(3,3-dimethylazetidin-1-yl)-5-fluoropyridin-3-yl]-2-fluorobenzylcarbamimidoylcarbamate,2-fluoro-3-(5-fluoro-6-{3-methyl-3-[(tetrahydropyran-2-yl)oxy]azetidin-1-yl}pyridin-3-yl)benzylcarbamimidoylcarbamate,2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate or2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 5. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(3-methoxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 6. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-{5-fluoro-6-[3-(methoxy-d3)azetidin-1-yl]pyridin-3-yl}benzylcarbamimidoylcarbamate.
 7. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 8. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(3-fluoroazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 9. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 10. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the compound is:2-fluoro-3-[5-fluoro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl]benzylcarbamimidoylcarbamate.
 11. The compound according to claim 1 or apharmacologically acceptable salt thereof, wherein the pharmacologicallyacceptable salt is a salt of an organic acid.
 12. The compound accordingto claim 1 or a pharmacologically acceptable salt thereof, wherein thepharmacologically acceptable salt is a salt of a dicarboxylic acid. 13.A pharmaceutical composition comprising the compound according to claim1, or a pharmacologically acceptable salt thereof, and at least one typeof pharmacologically acceptable additive.
 14. The compound of claim 1,wherein R1 and R2 are the same.
 15. The compound of claim 1, wherein R1and R2 are different.